Fluorine containing amino acids : synthesis and peptide coupling of amino acids containing the all-cis tetrafluorocyclohexyl motif

MA thanks the Egyptian Government for a Scholarship. DO’H thanks the Royal Society for a Royal Society Wolfson Research Merit Award.A synthesis of two (S)-phenylalanine derivatives is described which have the all-cis, 2,3,5,6-tetrafluorocyclohexyl motif attached to the aromatic ring at the meta and para positions; the para substituted isomer is elaborated into illustrative dipeptides via the free amine and carboxylate respectively demonstrating its utility as a novel amino acid for peptide synthesis and offering a vehicle for incorporation of this unique and facially polarized ring system into bioactive compounds.PostprintPeer reviewe

Selectively fluorinated cyclohexane building blocks : derivatives of carbonylated all-cis-3-phenyl-1,2,4,5-tetrafluorocyclohexane

MA thanks the Egyptian Government for a Scholarship under the Channel Scheme and we are grateful to the support of Professor L. Fathey of the University of Alexandria, Department of Chemistry, Egypt. DO'H thanks the Royal Society for a Wolfson Research Merit Award and we also thank the EPSRC Mass Spectrometry Service at Swansea University, UK for analyses.Palladium catalysed carbonylation reactions using the meta- and para-iodo derivatives of all-cis-3-phenyl-1,2,4,5-tetrafluorocyclohexane ( 4 ) are illustrated as the start point for a variety of functional group interconversions. The resultant benzaldehyde and benzoic acids offer novel building blocks for further derivatisation and facilitate the incorporation of the facially polarised all-cis-1,2,4,5-tetrafluorocyclohexane motif into more advanced molecular scaffolds.Publisher PDFPeer reviewe

Enantioselective synthesis in continuous flow : polymer supported isothiourea-catalyzed enantioselective Michael addition-cyclization with α-azol-2-ylacetophenones

Engineering and Physical Sciences Research Council - EP/W007517, EP/T023643/1A packed reactor bed incorporating a polymer-supported isothiourea HyperBTM catalyst derivative has been used to promote the enantioselective synthesis of a range of heterocyclic products derived from α-azol-2-ylacetophenones and -acetamides combined with alkyl, aryl, and heterocyclic α,β-unsaturated homoanhydrides in continuous flow via an α,β-unsaturated acyl-ammonium intermediate. The products are generated in good to excellent yields and generally in excellent enantiopurity (up to 97:3 er). Scale-up is demonstrated on a 15 mmol scale, giving the heterocyclic product in 68% overall yield with 98:2 er after recrystallization.Peer reviewe

Benzo[d][1,2,3]oxadithiole 2-oxide

Funding: A.G. thanks the Commissionerate of College Education, Government of Rajasthan for the generous support of a Foreign Training Program under its Teachers' Interface for Excellence Scheme.A simplified synthesis of the title compound is reported and its 1H and 13C NMR data are fully assigned including determination of H–H and C–H coupling constants. Its X-ray structure has been determined for the first time. NMR data are also presented for the oxygen analogue.Peer reviewe

Synthesis, structure, and reactivity of zwitterionic divalent rare-earth metal silanides

The synthesis and structures of the first zwitterionic divalent rare-earth metal silanides of the formula [Si(SiMe2OMe)3-κ3]2M (M-3), where M = Eu, Yb, and Sm, are reported. M-3 compounds feature spirocyclic bicyclooctane structures in which the central rare-earth metal ions are being octahedrally coordinated by six methoxy groups. The reaction of Yb-3 with BPh3 and W(CO)6 respectively generated the trinuclear zwitterions [Ph3BSi(SiMe2OMe)3-κ3]2Yb (Yb-4) and [(CO)5WSi(SiMe2OMe)3-κ3]2Yb (Yb-5) in good yield.PostprintPeer reviewe

Direct syntheses of stereoisomers of 3-fluoro GABA and β-fluoroamine analogues of the calcium receptor (CaR) agonists, cinacalcet, tecalcet, fendilines and NPS R-467

Synthetic routes following a sequential MacMillan organocatalytic asymmetric α-fluorination protocol for aldehydes and then reductive amination, have allowed ready access to bioactive β-fluoroamines. The approach is demonstrated with a short synthesis of (S)-3-fluoro-γ-aminobutyric acid (3F-GABA) and was extended to β-fluoroamine stereoisomers of cinacalcet, tecalcet, fendiline and NPS R-467, all allosteric modulators of the calcium receptor (CaR). Stereoisomers of the fluorinated calcimimetic analogues were then assayed in a CaR receptor assay and a comparison of β-fluoroamine matched pair stereoisomers revealed a binding mode preference to the receptor as deduced from conformations which will be favoured as a consequence of the electrostatic gauche effect.Publisher PDFPeer reviewe

Structure determination and Hirshfeld surface analysis of new cocrystal and salt forms of 5-aminotetrazole with hydroxy- and nitro-substituted carboxylic acids

Two new crystalline solids, namely, 5-amino­tetra­zole–3,5-di­hydroxy­benzoic acid–water (1/4/6), CH3N5·4C7H6O4·6H2O (I), and 5-amino­tetra­zolium 3,5-di­nitro­salicylate, CH4N5+·C7H3N2O7− (II), have been synthesized and characterized by single-crystal X-ray diffraction and Hirshfeld surface analysis. The crystal packing arrangements of I and II are governed by N—H⋯O and O—H⋯O hydrogen-bonding inter­actions. In cocrystal I, adjacent acid mol­ecules are linked through O—H⋯O hydrogen bonds, forming a dimer with an R22(8) motif. In salt II, the tetra­zolium cation and acid anion are linked through N—H⋯O hydrogen bonds to also form a dimer with an R22(8) motif. Further N—H⋯O and O—H⋯O hydrogen bonds help to stabilize the crystal packing, along with aromatic π–π stacking inter­actions in I and carbon­yl⋯π inter­actions in II. The Hirshfeld surface analysis and fingerprint plots reveal that O⋯H/H⋯O inter­actions contribute 34.4% of the total inter­actions in the crystal packing of cocrystal I and 36.7% in salt II.Publisher PDFPeer reviewe

6-exo-trig Michael addition-lactonizations for catalytic enantioselective chromenone synthesis

The authors thank the EPSRC Centre for Doctoral Training in Critical Resource Catalysis (CRITICAT, grant code EP/L016419/1, RMNP) for funding.The European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013) ERC Grant Agreement No. 279850 is also acknowledged. ADS thanks the Royal Society for a Wolfson Research Merit AwardThe catalytic enantioselective 6-exo-trig Michael addition-lactonization of enone-acid substrates to form cis-chromenones with high diastereo- and enantiocontrol was developed using the commercially available isothiourea tetramisole. An acidic workup proved necessary to minimize product epimerization and maximize product er, providing cis-chromenones in excellent yield, and with excellent diastereo- and enantioselectivity.Publisher PDFPeer reviewe

Application of four-membered ring chalcogenation reagents to the synthesis of new phosphorus-chalcogen heterocycles

The authors are grateful to the University of St Andrews for financial support.The reaction of four-membered ring chalcogenation reagents such as Lawesson’s reagent, 2,4-diferrocenyl-1,3,2,4-diathiadiphosphetane 2,4-disulfide (the ferrocene analogy of Lawesson’s reagent) and Woollins’ reagent with alkyl- or aryl-dithiols in refluxing toluene gave a series of five- to seven-membered organo-phosphorus-chalcogen heterocycles in 24% to 87% yields. Five representative X-ray structures confirm the formation of these five- to seven-membered heterocycles.Publisher PDFPeer reviewe

A low-spin CoII/Nitroxide complex for distance measurements at Q-band frequencies

Funding: AG was supported by the EPSRC funded Centre for Doctoral Training in ‘integrated magnetic resonance’, iMR-CDT (EP/J500045/1) the time the research was conducted. BEB is supported by the Leverhulme Trust (RPG-2018–397) and equipment funding from BBSRC (BB/R013780/1 and BB/T017740/1).Pulse dipolar electron paramagnetic resonance spectroscopy (PDS) is continuously furthering the understanding of chemical and biological assemblies through distance measurements in the nanometer range. New paramagnets and pulse sequences can provide structural insights not accessible through other techniques. In the pursuit of alternative spin centers for PDS, we synthesized a low-spin CoII complex bearing a nitroxide (NO) moiety, where both the CoII and NO have an electron spin S of 1/2. We measured CoII-NO distances with the well-established double electron–electron resonance (DEER aka PELDOR) experiment, as well as with the five- and six-pulse relaxation-induced dipolar modulation enhancement (RIDME) spectroscopies at Q-band frequencies (34 GHz). We first identified challenges related to the stability of the complex in solution via DEER and X-ray crystallography and showed that even in cases where complex disproportionation is unavoidable, CoII-NO PDS measurements are feasible and give good signal-to-noise (SNR) ratios. Specifically, DEER and five-pulse RIDME exhibited an SNR of ~100, and while the six-pulse RIDME exhibited compromised SNR, it helped us minimize unwanted signals from the RIDME traces. Last, we demonstrated RIDME at a 10 μM sample concentration. Our results demonstrate paramagnetic CoII to be a feasible spin center in medium magnetic fields with opportunities for PDS studies involving CoII ions.Publisher PDFPeer reviewe