Organic & Biomolecular Chemistry (v.14, #25)

Front cover (5865-5865).

Inside front cover (5866-5866).

Contents list (5867-5874).

Recent applications in natural product synthesis of dihydrofuran and -pyran formation by ring-closing alkene metathesis by Reece Jacques; Ritashree Pal; Nicholas A. Parker; Claire E. Sear; Peter W. Smith; Aubert Ribaucourt; David M. Hodgson (5875-5893).
In the past two decades, alkene metathesis has risen in prominence to become a significant synthetic strategy for alkene formation. Many total syntheses of natural products have used this transformation. We review the use, from 2003 to 2015, of ring-closing alkene metathesis (RCM) for the generation of dihydrofurans or -pyrans in natural product synthesis. The strategies used to assemble the RCM precursors and the subsequent use of the newly formed unsaturation will also be highlighted and placed in context.

Total synthesis, biosynthesis and biological profiles of clavine alkaloids by Stephanie R. McCabe; Peter Wipf (5894-5913).
This review highlights noteworthy synthetic and biological aspects of the clavine subfamily of ergot alkaloids. Recent biosynthetic insights have laid the groundwork for a better understanding of the diverse biological pathways leading to these indole derivatives. Ergot alkaloids were among the first fungal-derived natural products identified, inspiring pharmaceutical applications in CNS disorders, migraine, infective diseases, and cancer. Pergolide, for example, is a semi-synthetic clavine alkaloid that has been used to treat Parkinson's disease. Synthetic activities have been particularly valuable to facilitate access to rare members of the Clavine family and empower medicinal chemistry research. Improved molecular target identification tools and a better understanding of signaling pathways can now be deployed to further extend the biological and medical utility of Clavine alkaloids.

Catalytic asymmetric [3 + 3] annulation of cyclopropanes with mercaptoacetaldehyde by Xuan Fu; Lili Lin; Yong Xia; Pengfei Zhou; Xiaohua Liu; Xiaoming Feng (5914-5917).
A highly diastereo- and enantioselective [3 + 3] annulation of donor–acceptor cyclopropanes with mercaptoacetaldehyde has been developed. In the presence of a N,N′-dioxide–Sc(iii) complex as the catalyst, a number of aromatic substituted cyclopropyl ketones reacted with mercaptoacetaldehyde smoothly, providing the corresponding chiral tetrahydrothiopyranols in moderate yields with excellent ee (up to 99% ee) and dr values (up to >19 : 1).

Selective inhibition of p97 by chlorinated analogues of dehydrocurvularin by Joseph Tillotson; Bharat P. Bashyal; MinJin Kang; Taoda Shi; Fabian De La Cruz; A. A. Leslie Gunatilaka; Eli Chapman (5918-5921).
The ATPase p97 is a ubiquitin targeted segregase that uses the energy of ATP binding and hydrolysis to extract ubiquitylated substrates from biological membranes, from other proteins, or from protein complexes to carry out myriad tasks in eukaryotes. Increased p97 activity has been linked to a poor prognosis in cancer patients, making p97 an anti-neoplastic target. In the present study, we show that dehydrocurvularin (DHC) and its chlorinated variants are covalent inhibitors of p97, interfering with its ATPase activity. Interestingly, cellular studies revealed both DHC and its monochloro analogue interfere with both the proteasome and p97, whereas its dichloro analogue showed p97 specificity.

Synthesis of annulated pyridines as inhibitors of aldosterone synthase (CYP11B2) by Rainer E. Martin; Johannes Lehmann; Thibaut Alzieu; Mario Lenz; Marjorie A. Carnero Corrales; Johannes D. Aebi; Hans Peter Märki; Bernd Kuhn; Kurt Amrein; Alexander V. Mayweg; Robert Britton (5922-5927).
A series of cyclopenta[c]pyridine aldosterone synthase (AS) inhibitors were conveniently accessed using batch or continuous flow Kondrat'eva reactions. Preparation of the analogous cyclohexa[c]pyridines led to the identification of a potent and more selective AS inhibitor. The structure-activity-relationship (SAR) in this new series was rationalized using binding mode models in the crystal structure of AS.

Cyclic peptide-based potent human SIRT6 inhibitors by Jiajia Liu; Weiping Zheng (5928-5935).
We discovered in the current study that six side chain-to-side chain cyclic pentapeptides harboring a central Nε-dodecyl (or tetradecyl)-thiocarbamoyl-lysine residue all behaved as highly potent (nM level) inhibitors against human SIRT6-catalyzed deacylation reaction. Moreover, one compound was also found to be selective for SIRT6 versus SIRT2/3/5 (∼20-, ∼11-, and >940-fold, respectively), despite its modest (∼2.3-fold) SIRT6 inhibitory selectivity versus SIRT1. These compounds could be valuable leads for the identification of further potent and selective human SIRT6 inhibitors.

KI-catalyzed α-acyloxylation of acetone with carboxylic acids by Ya-Dong Wu; Bei Huang; Yue-Xin Zhang; Xiao-Xu Wang; Jian-Jun Dai; Jun Xu; Hua-Jian Xu (5936-5939).
The KI-catalyzed reaction of acetone with aromatic carboxylic acids is achieved, leading to α-acyloxycarbonyl compounds in good to excellent yields under mild reaction conditions. The present method exhibits good functional-group compatibility. Notably, this reaction system is even suitable for cinnamic acid, 3-phenylpropiolic acid and 4-phenylbutanoic acid. A kinetic isotope effect (KIE) study indicates that C–H cleavage of the acetone is the rate-limiting step in the catalytic cycle.

Cs2CO3 as a source of carbonyl and ethereal oxygen in a Cu-catalysed cascade synthesis of benzofuran [3,2-c] quinolin-6[5-H]ones by Wajid Ali; Anju Modi; Ahalya Behera; Prakash Ranjan Mohanta; Bhisma K. Patel (5940-5944).
The simultaneous construction of C–C, C–O, and C–N bonds utilizing Cs2CO3 as a source of both carbonyl (CO) and ethereal oxygen and a cascade synthesis of benzofuro[3,2-c]quinolin-6(5H)-one have been achieved using a combination of Cu(OAc)2 and Ag2CO3. A plausible mechanism has been proposed for this unprecedented transformation.

A Rh-catalysed [5 + 1] cycloaddition of allenylcyclopropanes and CO has been developed to synthesize functionalized 2-methylidene-3,4-cyclohexenones. The scope of this methodology has been investigated, showing that various functional groups can be tolerated. Both di- and tri-substituted allenylcyclopropanes can be applied to this cycloaddition and the [5 + 1] cycloadducts with the E configuration were obtained as the major products. In addition, the present [5 + 1] cycloaddition reaction has been utilized as a key step in the formal synthesis of the natural product (−)-galanthamine.

Enol ethers as carbonyl surrogates in a modification of the Povarov synthesis of 3-aryl quinolines and their anti-Toxoplasma activity by Carla E. Brown; James McNulty; Claudia Bordón; Robert Yolken; Lorraine Jones-Brando (5951-5955).
A novel method for the preparation of 2-carboxyl-3-aryl quinoline derivatives from anilines, ethyl glyoxalate and enol ethers as phenylacetaldehyde surrogates is reported. The three-component coupling reaction occurs rapidly under mild conditions in dichloromethane catalysed by TFA. The method allows a more direct access to 3-aryl quinolines, sidestepping issues encountered with phenylacetaldehyde derivatives. This chemistry was used to prepare quinolines with 3-diarylether functionality that showed low micromolar efficacy (IC50 range: 5–26 μM) against in vitro Toxoplasma gondii coupled with little or no cytotoxicity (TD50≥ 320 μM) towards the host cells.

A novel smart supramolecular organic gelator exhibiting dual-channel responsive sensing behaviours towards fluoride ion via gel–gel states by Hassan Mehdi; Hongchang Pang; Weitao Gong; Manivannan Kalavathi Dhinakaran; Ali Wajahat; Xiaojun Kuang; Guiling Ning (5956-5964).
A novel smart supramolecular organic gelator G-16 containing anion and metal-coordination ability has been designed and synthesized. It shows excellent and robust gelation capability as a strong blue fluorescent supramolecular organic gel OG in DMF. Addition of Zn2+ produced Zn2+-coordinated supramolecular metallogel OG-Zn. Organic gel OG and organometallic gel OG-Zn exhibited efficient and different sensing behaviors towards fluoride ion due to the variation in self-assembling nature. Supramolecular metallogel OG-Zn displayed specific selectivity for fluoride ion and formed OG-Zn-F with dramatic color change from blue to blue green in solution and gel to gel states. Furthermore after directly addition of fluoride into OG produced fluoride containing organic gel OG-F with drastically modulation in color from blue to greenish yellow fluorescence via strong aggregation-induced emission (AIE) property. A number of experiments were conducted such as FTIR, 1H NMR, and UV/Vis spectroscopies, XRD, SEM and rheology. These results revealed that the driving forces involved in self-assembly of OG, OG-Zn, OG-Zn-F and OG-F were hydrogen bonding, metal coordination, π–π interactions, and van der Waal forces. In contrast to the most anion responsive gels, particularly fluoride ion responsive gels showed gel–sol state transition on stimulation by anions, the gel state of OG and OG-Zn did not show any gel-to-sol transition during the whole F response process.

Cyclopropane rings are versatile building blocks in organic chemistry. Their synthesis, by the reaction of sulfur ylides with α,β-unsaturated carbonyl compounds, has recently aroused renewed interest after the discovery of efficient catalysis by using (S)-indoline-2-carboxylic acid. In order to rationalize the behavior of this catalyst, MacMillan proposed a directed electrostatic activation (DEA) mechanism, in which the negative carboxylate group interacts with the positive thionium moiety, thus reducing the activation energy and increasing the reaction rate. More recently, Mayr refuted some of MacMillan conclusions, but accepted the DEA mechanism as a justification for the experimental high reaction rates. In contrast, our results indicate that the selectivity obtained in the process seems to result from several strong hydrogen bond interactions between the two reacting species, while no strong evidence for a DEA mechanism was found. We also concluded that the hydrogen bonds don't improve the reaction rate by lowering the activation energy of the rate-determining step, but can do it by promoting efficient reaction trajectories due to long-range complexation of the reagents. Finally, our results confirm that the cyclopropanation reaction occurs by a two-step mechanism, and that the overall enantioselectivity depends on the relative energies of the two steps, averaged by the relative populations of the iminium intermediates that are initially formed in the reaction.

Synthesis of trifluoromethylated isoxazoles and their elaboration through inter- and intra-molecular C–H arylation by Jian-Siang Poh; Cristina García-Ruiz; Andrea Zúñiga; Francesca Meroni; David C. Blakemore; Duncan L. Browne; Steven V. Ley (5983-5991).
We report conditions for the preparation of a range of trifluoromethylated isoxazole building blocks through the cycloaddition reaction of trifluoromethyl nitrile oxide. It was found that controlling the rate (and therefore concentration) of the formation of the trifluoromethyl nitrile oxide was Critical for the preferential formation of the desired isoxazole products versus the furoxan dimer. Different conditions were optimised for both aryl- and alkyl-substituted alkynes. In addition, the reactivity at the isoxazole 4-position has been briefly explored for these building blocks. Conditions for intermolecular C–H arylation, lithiation and electrophile quench, and alkoxylation were all identified with brief substrate scoping that signifies useful tolerance to a range of functionalities. Finally, complementary processes for structural diversification through either intramolecular cyclisation or intermolecular cross-coupling were developed.

Synthesis and determination of absolute configuration of a non-peptidic αvβ6 integrin antagonist for the treatment of idiopathic pulmonary fibrosis by Niall A. Anderson; Ian B. Campbell; Brendan J. Fallon; Sean M. Lynn; Simon J. F. Macdonald; John M. Pritchard; Panayiotis A. Procopiou; Steven L. Sollis; Lee R. Thorp (5992-6009).
A diastereoselective synthesis of (S)-3-(3-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid (1), a potential therapeutic agent for the treatment of Idiopathic Pulmonary Fibrosis, which is currently undergoing Phase I clinical trials is reported. The key steps in the synthesis involved alkylation of 2-methylnaphthyridine with (R)-N-Boc-3-(iodomethyl)-pyrrolidine, and an asymmetric Rh-catalysed addition of an arylboronic acid to a 4-(N-pyrrolidinyl)crotonate ester. The overall yield of the seven linear step synthesis was 8% and the product was obtained in >99.5% ee proceeding with 80% de. The absolute configuration of 1 was established by an alternative asymmetric synthesis involving alkylation of an arylacetic acid using Evans oxazolidinone chemistry, acylation using the resulting 2-arylsuccinic acid, and reduction. The absolute configuration of the benzylic asymmetric centre was established as (S).

The discovery of allyltyrosine based tripeptides as selective inhibitors of the HIV-1 integrase strand-transfer reaction by Neal Dalton; Christopher P. Gordon; Timothy P. Boyle; Nicholas Vandegraaf; John Deadman; David I. Rhodes; Jonathan A. Coates; Stephen G. Pyne; Paul A. Keller; John B. Bremner (6010-6023).
From library screening of synthetic antimicrobial peptides, an O-allyltyrosine-based tripeptide was identified to possess inhibitory activity against HIV-1 integrase (IN) exhibiting an IC50 value of 17.5 μM in a combination 3′-processing and strand transfer microtitre plate assay. The tripeptide was subjected to structure–activity relationship (SAR) studies with 28 peptides, incorporating an array of natural and non-natural amino acids. Resulting SAR analysis revealed the allyltyrosine residue was a key feature for IN inhibitory activity whilst incorporation of a lysine residue and extended hydrophilic chains bearing a terminal methyl ester was advantageous. Addition of hydrophobic aromatic moieties to the N-terminal of the scaffold afforded compounds with improved inhibitory activity. Consolidation of these functionalities lead to the development of the tripeptide 96 which specifically inhibited the IN strand-transfer reaction with an IC50 value of 2.5 μM.

Asymmetric aza-Morita–Baylis–Hillman reactions of chiral N-phosphonyl imines with acrylates via GAP chemistry/technology by Bing Yang; Xiaozhou Ji; Yunsheng Xue; Haowei Zhang; Minxing Shen; Bo Jiang; Guigen Li (6024-6035).
Chiral N-phosphonyl imines have been proven to be efficient electrophilic acceptors for asymmetric aza-Morita–Baylis–Hillman (aza-MBH) reactions with acrylates under convenient conditions. Thirty examples of β-amino acrylates were generated in high yields (up to 99.4%) and diastereoselectivity (up to >99 : 1 dr) in an atom-economical fashion. The synthesis was proved to follow the GAP (group-assisted purification) chemistry, i.e., the pure products can be obtained simply by washing the crude products with hexane/ethyl acetate (v/v, 10/1) without the use of chromatography or recrystallization. DFT calculations were also conducted to support an asymmetric induction model accounting for high diastereoselectivity.

Cyclomarins are cyclic heptapeptides containing four unusual amino acids. New synthetic protocols toward their synthesis have been developed, leading to the synthesis and biological evaluation of three natural occurring cyclomarins. Interestingly, cyclomarins address two completely different targets: Clp C1, a subunit of the caseinolytic protease of Mycobacterium tuberculosis (MTB), as well as PfAp3Ase of Plasmodium falciparum. Therefore, cyclomarins are interesting lead structures for the development of drugs against tuberculosis and malaria.

Total synthesis of desoxycyclomarin C and the cyclomarazines A and B by Philipp Barbie; Uli Kazmaier (6055-6064).
Removing the β-hydroxy group from the prenylated tryptophan moiety of cyclomarins simplifies the synthesis of these interesting natural products significantly, without having a noteworthy effect on the anti-tuberculosis activity of the cyclomarins. In contrast, cyclomarazines did not show biological activity.

Synthesis of furo[3,2-c]coumarin derivatives using visible-light-promoted radical alkyne insertion with bromocoumarins by Hui Zhou; Xinzhao Deng; Zhenjun Ma; Aihua Zhang; Qixue Qin; Ren Xiang Tan; Shouyun Yu (6065-6070).
The synthesis of privileged structures, which are potent drug candidates, is an impetus for drug discovery. The construction of heterocyclic framework furo[3,2-c]coumarins using a visible-light promoted photoredox neutral coupling of 3-bromo-4-hydroxycoumarins with commercially available alkynes has been reported. These reactions can be carried out at room temperature under visible light irradiation with good chemical yields. This work presents 17 furocoumarins, 12 of which are new. Three of the newly synthesized compounds show potent cytotoxicity, and one shows moderate acetylcholinesterase inhibitory activity with IC50 values of 2.16 ± 0.13 μM.

A systematic study of protein labeling by fluorogenic probes using cysteine targeting vinyl sulfone-cyclooctyne tags by B. Söveges; T. Imre; T. Szende; Á. L. Póti; G. B. Cserép; T. Hegedűs; P. Kele; K. Németh (6071-6078).
Fluorescent tagging of proteins via accessible cysteine residues is of paramount importance. In this study, model proteins of interest (mitogen-activated protein kinases) were labeled successfully in native state on their free thiols by direct fluorescence derivatization, or in a sequential manner where conjugation of the site specific linker and the fluorophore is carried out in two steps. To this end we designed and prepared two novel chemical reporters carrying vinyl sulfone as Cys targeting function and cyclooctyne motifs, suitable for subsequent conjugation with fluorogenic azides via copper free strain-promoted azide–alkyne click chemistry. Direct and sequential labeling reaction steps were analyzed by native PAGE, capillary zone electrophoresis and tandem mass spectrometry. The efficiency of tagging was correlated with solvent accessibility of the Cys residues. Our results indicated that conjugation of native proteins by vinyl sulfone linkers was fast and thiol-selective. Subsequent click reaction with fluorogenic dyes generates intensive fluorescence signals and fulfills all requirements of bioorthogonality.

Alkyl substituted [2.2]paracyclophane-1,9-dienes by Benjamin J. Lidster; Dharam R. Kumar; Andrew M. Spring; Chin-Yang Yu; Madeleine Helliwell; James Raftery; Michael L. Turner (6079-6087).
[2.2]Paracyclophane-1,9-dienes substituted with n-octyl chains have been synthesised from the corresponding dithia[3.3]paracyclophanes using a benzyne induced Stevens rearrangement. The use of 2-(trimethylsilyl)phenyl trifluoromethanesulfonate and tetra-n-butylammonium fluoride as the in situ benzyne source gave significantly improved yields over traditional sources of benzyne and enabled the preparation of n-octyl substituted [2.2]paracyclophane-1,9-dienes on a multi-gram scale.

Synthesis of misfolded glycoprotein dimers through native chemical ligation of a dimeric peptide thioester by Masayuki Izumi; Shinji Komaki; Ryo Okamoto; Akira Seko; Yoichi Takeda; Yukishige Ito; Yasuhiro Kajihara (6088-6094).
Glycoprotein quality control processes are very important for an efficient production of glycoproteins and for avoiding the accumulation of unwanted toxic species in cells. These complex processes consist of multiple enzymes and chaperones such as UGGT, calnexin/calreticulin, and glucosidase II. We designed and synthesized monomeric and dimeric misfolded glycoprotein probes. Synthetic homogeneous monomeric glycoproteins proved to be useful substrates for kinetic analyses of the folding sensor enzyme UGGT. For a concise synthesis of a bismaleimide-linked dimer, we examined double native chemical ligation (dNCL) of a dimeric peptide-α-thioester. The dNCL to two equivalents of glycopeptides gave a homodimer. The dNCL to a 1 : 1 mixture of a glycopeptide and a non-glycosylated peptide gave all the three possible ligation products consisting of two homodimers and a heterodimer. Both the homodimer bearing two Man9GlcNAc2 (M9) oligosaccharides and the heterodimer bearing one M9 oligosaccharide were found to be good substrates of UGGT.

Exploiting the σ-phylic properties of cationic gold(i) catalysts in the ring opening reactions of aziridines with indoles by Elisabetta Rossi; Giorgio Abbiati; Monica Dell'Acqua; Marco Negrato; Andrea Paganoni; Valentina Pirovano (6095-6110).
A study on the SN2-type ring opening reactions of aziridines with indoles as nucleophiles is reported. Under gold(i) catalysis a great variety of tryptamine derivatives were prepared in good to excellent yields with complete stereocontrol when chiral aziridines were used. We demonstrated that cationic gold(i) catalysts are superior Lewis acids to the previously reported group 3, 12 and 13 metals in terms of catalyst loading and reaction yields. Moreover, complete regioselectivity was observed for 2-phenyl-N-tosylaziridine; whereas, regioselectivity up to 10 : 1 ratio was observed with 2-methyl-N-tosylaziridine. Finally, a preliminary study on the dearomatization reactions giving rise to pyrroloindolines is also reported.

Cooperative cascade catalysis by bovine serum albumin (BSA)–iodine allows for the first time the performance of C(sp2)–H sulfenylation of indole from readily available thiophenol (–SH bond) via in situ generation/cleavage of disulfide (S–S bond) in air under aqueous conditions, whereas BSA or I2 individually do not permit this two step sequence to occur in the same pot towards C–S bond formation. This green cooperative protocol is extendable to sulfenylation of hydroxyaryls (i.e. 2-naphthol or 4-hydroxycoumarin) with diverse thiols (aryl/heteroaryl) without using any toxic metal catalysts, bases or oxidants, thus rendering the process environmentally and economically reliable. Further, the gram scale synthesis of a COX-2 inhibitor (3-(pyridin-2-ylthio)-1H-indole), regioselectivity and recyclability (up to four cycles) are the additional merits of this cooperative cascade bio-chemocatalytic (BSA–I2) protocol. Moreover, HPLC and ESI-MS provide powerful insights into the mechanistic aspects of the above cascade sulfenylation reaction.

Synthesis and evaluation of new 2-aminothiophenes against Mycobacterium tuberculosis by Sandeep Thanna; Susan E. Knudson; Anna Grzegorzewicz; Sunayana Kapil; Christopher M. Goins; Donald R. Ronning; Mary Jackson; Richard A. Slayden; Steven J. Sucheck (6119-6133).
Tuberculosis (TB) and its drug resistant forms kills more people than any other infectious disease. This fact emphasizes the need to identify new drugs to treat TB. 2-Aminothiophenes (2AT) have been reported to inhibit Pks13, a validated anti-TB drug target. We synthesized a library of 42 2AT compounds. Among these, compound 33 showed remarkable potency against Mycobacterium tuberculosis (Mtb) H37RV (MIC = 0.23 μM) and showed an impressive potency (MIC = 0.20–0.44 μM) against Mtb strains resistant to isoniazid, rifampicin and fluoroquinolones. The site of action for the compound 33 is presumed to be Pks13 or an earlier enzyme in the mycolic acid biosynthetic pathway. This inference is based on structural similarity of the compound 33 with known Pks13 inhibitors, which is corroborated by mycolic acid biosynthesis studies showing that the compound strongly inhibits the biosynthesis of all forms of mycolic acid in Mtb. In summary, these studies suggest 33 represents a promising anti-TB lead that exhibits activity well below toxicity to human monocytic cells.

Back cover (6135-6136).