Blooms of the microalga Prymnesium parvum cause devastating fish kills worldwide, which are suspected to be caused by the supersized ladder-frame polyether toxins prymnesin-1 and -2. These toxins have, however, only been detected from P. parvum in rare cases since they were originally described two decades ago. Here, we report the isolation and characterization of a novel B-type prymnesin, based on extensive analysis of 2D- and 3D-NMR data of natural as well as 90% 13C enriched material. B-type prymnesins lack a complete 1,6-dioxadecalin core unit, which is replaced by a short acyclic C2 linkage compared to the structure of the original prymnesins. Comparison of the bioactivity of prymnesin-2 with prymnesin-B1 in an RTgill-W1 cell line assay identified both compounds as toxic in the low nanomolar range. Chemical investigations by liquid chromatography high-resolution mass spectrometry (LC-HRMS) of 10 strains of P. parvum collected worldwide showed that only one strain produced the original prymnesin-1 and -2, whereas four strains produced the novel B-type prymnesin. In total 13 further prymnesin analogues differing in their core backbone and chlorination and glycosylation patterns could be tentatively detected by LC-MS/HRMS, including a likely C-type prymnesin in five strains. Altogether, our work indicates that evolution of prymnesins has yielded a diverse family of fish-killing toxins that occurs around the globe and has significant ecological and economic impact.

Chemodiversity of Ladder-Frame Prymnesin Polyethers in Prymnesium parvum

Silas Anselm Rasmussen†, Sebastian Meier‡, Nikolaj Gedsted Andersen§, Hannah Eva Blossom§, Jens Øllgaard Duus‡, Kristian Fog Nielsen†, Per Juel Hansen*§, and Thomas Ostenfeld Larsen*†

† Department of Biotechnology and Biomedicine, Technical University of Denmark, Søltofts Plads 221, 2800 Kgs. Lyngby,Denmark

‡ Department of Chemistry, Technical University of Denmark, Kemitorvet 207, 2800 Kgs. Lyngby, Denmark

§ Marine Biological Section, Department of Biology, Copenhagen University, Strandpromenaden 5, 2100 Helsingør,Denmark

J. Nat. Prod., Article ASAP

DOI: 10.1021/acs.jnatprod.6b00345

Publication Date (Web): August 23, 2016

Copyright © 2016 The American Chemical Society and American Society of Pharmacognosy

*Tel (P. J. Hansen): (+45) 35321985. E-mail: pjhansen@bio.ku.dk., *Tel (T. O. Larsen): (+45) 45252632. E-mail: tol@bio.dtu.dk.

http://pubs.acs.org/doi/full/10.1021/acs.jnatprod.6b00345

 

Figure 1. LC-MS/HRMS screening of 10 P. parvum strains. (A) Summed EICs (doubly charged) of all prymnesin-like molecules in 10 worldwide-distributed strains of P. parvum. Green EIC was created for original prymnesin-1 and -2. Red EICs show B-type prymnesins. Blue EICs show tentatively identified C-type prymnesins. (B) MS/HRMS spectra of [M + 2H]2+: (top) prymnesin-1 and -2, (middle) prymnesin-B1 and -B2, (bottom) tentatively assigned C-type prymnesins. Δ66 shows a loss of a pentose (m/z 66.021, doubly charged) and Δ81 a loss of a hexose (m/z 81.026, doubly charged). Asterisk (*) denotes tentatively characterized by MS/MS, UV, and chiral-phase GC-MS.

aChemical shifts are reported in CD3OD and referenced to δH 3.31 ppm and δC 47.9 ppm at 313 K. n.d. = not detected.

 

////////////Chemodiversity, Ladder-Frame, Prymnesin Polyethers, Prymnesium parvum

aChemical shifts are reported in CD3OD and referenced to δH 3.31 ppm and δC 47.9 ppm at 313 K. n.d. = not detected.

 

////////////Chemodiversity, Ladder-Frame, Prymnesin Polyethers, Prymnesium parvum

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ATOVAQUONE SPECTRAL VISIT

ATOVAQUONE



FIRST ONE............FROM NET





http://pubs.acs.org/doi/abs/10.1021/op500032w

mp 219–221 °C;

 IR (KBr) ν 728, 822, 1089, 1278, 1347, 1369, 1490, 1595, 1659, 2855, 2926, 3377 cm–1; 

1H NMR (CDCl3 with 0.03% TMS, 400 MHz): δ 8.08–8.16 (m, 2H), 7.68–7.80 (m, 2H), 7.55 (s, 1H), 7.27–7.29 (d, 2H), 7.18–7.20 (d, 2H), 3.15–3.23 (tt, 1H), 2.62–2.69 (tt, 1H), 2.16–2.26 (m, 2H), 1.97–2.01 (m, 2H), 1.77–1.80 (m,2H), 1.54–1.65 (m, 2H). 

The HPLC analysis using hypersil BDS, acetonitrile/water/methanol/ortho-phosphoric acid (525:300:175:5), 3 mL/min, 25 °C, confirmed the purity of atovaquone to be more than 99.8%, without a detectable amount of cis-isomer and no other single impurity more than 0.05%.






SECOND ONE............


http://pubs.acs.org/doi/abs/10.1021/op300165q

13c NMR CDCL3 ABOVE

1H NMR (400 MHz, CDCl3): δH 1.48–1.64 (2H, m), 1.71–1.78 (2H, m), 1.92–2.02 (2H, m), 2.13–2.25 (2H, m), 2.64 (1H, m), 3.17 (1H, m), 7.18 (2H, d), 7.27 (2H, d), 7.48 (1H, s, OH), 7.68 (1H, m), 7.76 (1H, m), 8.08 (1H, d) and 8.14 (1H, d); 

13C NMR (100 MHz, CDCl3): δC29.2, 34.4, 34.5, 43.2, 126.0, 127.0, 127.3, 128.2, 128.4, 129.2, 131.5, 132.8, 133.2, 135.0, 146.0, 153.0, 181.8, 184.5; 

HRMS (APCI, negative ion, [M – H]−) calculated for C22H18ClO3 365.0950, found 365.0951.






THIRD ONE..............

http://nopr.niscair.res.in/bitstream/123456789/21838/1/IJCB%2052B(10)%201299-1312.pdf

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1-Benzyl-3-(tert-butyl)-4-phenylazetidin-2-one

1-Benzyl-3-(tert-butyl)-4-phenylazetidin-2-one. dr trans/cis 95:5. Trans-6e,
colourless oil,


1H NMR (600 MHz, CDCl3) 
1.00 (s, 9H), 2.87 (dd, J = 2.1, 0.72Hz, 1H), 3.67 (d, J = 14.9 Hz, 1H), 4.14 (d, J = 2.2 Hz, 1H), 4.91 (d, J = 14.9 Hz, 1H),7.14 – 7.16 (m, 2H), 7.24 – 7.25 (m, 2H), 7.27 – 7.34 (m. 4H), 7.36 – 7.38 (m, 2H).


13C NMR (150.0 MHz, CDCl3) 
 27.2, 31.7, 44.0, 56.4, 71.3, 126.5, 127.5, 128.1,128.5, 128.6, 128.9, 135.8, 138.3, 169.2. 

IR (neat, cm-1) 2960, 1728, 1403, 1362,729, 701.

 HRMS m/z calculated for C20H24NO [M + H]+ 294.1858 found 294.1861.

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2-chloro-5-(((E)-2-(((E)-2,2,2-trifluoroethylidene)hydrazono)imidazolidin-1-yl)methyl)pyridi ne

2-chloro-5-(((E)-2-(((E)-2,2,2-trifluoroethylidene)hydrazono)imidazolidin-1-yl)methyl)pyridi ne (5):

white solid, mp 114–115 o C;

1 H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 2.2 Hz, 1H), 7.68 (q, J = 8.0, Hz, 1H), 7.48 (q, J = 4.5 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 5.88 (s, 1H), 4.50 (s, 2H), 3.55 (t, J = 7.8 Hz, 2H), 3.46 – 3.40 (m, 2H); 19F NMR (376 MHz, CDCl3) δ –66.13 (d, J = 4.5 Hz);

13C NMR (100 MHz, CDCl3) δ 165.04, 150.86, 149.32, 134.55 (q, JC-F = 35.63 Hz), 131.37, 124.45, 121.27 (q, JC-F = 268.16 Hz) 46.83, 45.14, 40.68;

IR (KBr) ν 2884.47, 1638.83, 1568.03, 1515.93, 1338.41, 1266.40, 1115.71, 1020.69, 896.58, 739.17, 593.14 cm-1 ;

HRMS (ESI) found: m/z 306.0726, [M+H]+ calcd. for C11H12ClF3N5 + 306.0728.




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(E)-1,3-bis(2,6-diisopropylphenyl)-2-((2,2,2-trifluoroethylidene)hydrazono)imidazolidine

(E)-1,3-bis(2,6-diisopropylphenyl)-2-((2,2,2-trifluoroethylidene)hydrazono)imidazolidine :

white solid; mp 133–134 o C;

1 H NMR (600 MHz, CDCl3) δ 7.28 (t, J = 7.4 Hz, 1H), 7.19 (t, J = 7.5 Hz, 1H), 7.14 (d, J = 7.5 Hz, 2H), 7.04 (d, J = 7.5 Hz, 2H), 6.85 (q, J = 4.2 Hz, 1H), 3.78 (s, 4H), 3.12 – 3.03 (m, 4H), 1.24 (t, J = 6.9 Hz, 12H), 1.16 (d, J = 6.6 Hz, 6H), 1.05 (d, J = 6.6 Hz, 6H);

19F NMR (565 MHz, CDCl3) δ –66.51 (d, J = 3.7 Hz);


13C NMR (150 MHz, CDCl3) δ 160.08, 147.72, 145.49, 137.54, 134.30, 133.60 (q, JC-F = 23.60 Hz), 129.10, 127.97, 124.29, 123.83, 121.17 (q, JC-F = 179.01 Hz), 51.45, 49.07, 29.21, 28.95, 24.71, 24.40, 24.02, 22.92;

IR (KBr) ν 2987.56, 1534, 1491, 1463, 1325, 1267, 934, 894 cm-1 ;

HRMS (ESI) found: m/z 501.3204, [M+H]+ calcd. for C29H40F3N4 + 501.3200.




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1-({[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl}oxy)pyrrolidine-2,5-dione

 1-({[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl}oxy)pyrrolidine-2,5-dione








 1-({[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl}oxy)pyrrolidine-2,5-dione



Synthesis of 1-({[(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl}oxy)pyrrolidine-2,5-dione (1)

GC analysis (assay of 1, heptylbenzene as an internal standard): DB-17 (0.25 mmφ × 30 m, 0.25 μm), flow rate = 2.4 mL/min, injection mode; split (1/50), injection temperature; 180 °C, column temperature; 110 °C (15 min) → 10 °C/min → 280 °C (8 min), detection temperature; 280 °C (FID), retention time; 8.5 min (heptylbenzene), 31.9 min (major diastereomer of 1), 32.0 min (minor diastereomer of 1).

HPLC analysis (optical purity): CHIRALPAK IA-3 (4.6 mm*250 mm, 3 μm), hexane/0.01% THF solution of TFA = 45:55, flow rate = 0.5 mL/min, detector; UV 254 nm, retention time; 9.3 min (minor), 11.9 min (major). 

1H NMR (400 MHz, CDCl3) δ 5.75 (1H, d, J = 4.8 Hz), δ 5.25 (1H, dt, J= 8.4, 6.0 Hz), δ 4.11 (1H, dd, J = 10.4, 6.4 Hz), δ 4.03 (1H, td, J = 8.8, 2.4 Hz), δ 3.97–3.91 (2H, m), δ 3.17–3.10 (1H, m), δ 2.86 (4H, s), δ 2.17–2.12 (1H, m), δ 2.04–1.93 (1H, m); 

13C NMR (100 MHz, CDCl3) δ 168.4, 151.1, 109.1, 79.6, 69.9, 69.6, 45.0, 25.9, 25.4; 

HRMS (ESI-HESI+) calcd for C11H17N2O7: 289.1030 ([M + NH4]+), found: 289.1028 ([M + NH4]+).

http://pubs.acs.org/doi/full/10.1021/acs.oprd.6b00178

Research and Development of an Efficient Synthesis of a Key Building Block for Anti-AIDS Drugs by Diphenylprolinol-Catalyzed Enantio- and Diastereoselective Direct Cross Aldol Reaction

Yumi Hayashi, Toshiaki Aikawa, Yasuharu Shimasaki, Hiroaki Okamoto, Yosuke Tomioka, Takashi Miki, Masahiro Takeda, and Tetsuya Ikemoto*

Health & Crop Sciences Research Laboratory, Sumitomo Chemical Co., Ltd., 1-21, Utajima 3-chome, Nishiyodogawa-ku, Osaka 555-0021, Japan

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00178

*E-mail address: ikemotot2@sc.sumitomo-chem.co.jp.

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SYNTHESIS Highlight

Image by Steven V. Ley and co-workers Augmented Reality: New perspectives for the visualization of molecules This SYNTHESIS paper highlights the combination of enabling technologies to improve the stereoselectivity of a Wolff–Staudinger cascade reaction. Read Article  ›

Synthesis
DOI: 10.1055/s-0035-1562579

paper

Combination of Enabling Technologies to Improve and Describe the Stereoselectivity of Wolff–Staudinger Cascade Reaction

B. Musioa, F. Mariania, b, E. P. Śliwińskia, M. A. Kabeshova, H. Odajimac, S. V. Ley*a

• aUniversity of Cambridge, Department of Chemistry, Lensfield Road, Cambridge, CB2 1EW, UK   Email:svl1000@cam.ac.uk
• bUniversitat de Barcelona, Laboratori de Química Orgànica, Facultat de Farmàcia, Av. Joan XXIII s/n, 08028 Barcelona, Spain
• cSaida FDS, 143-10 Itsushiki, Yaizu-shi, Shizuoka Prefecture 4250054, Japan

https://www.thieme-connect.de/products/ejournals/html/10.1055/s-0035-1562579?update=true

Abstract

A new, single-mode bench-top resonator was evaluated for the microwave-assisted flow generation of primary ketenes by thermal decomposition of α-diazoketones at high temperature. A number of amides and β-lactams were obtained by ketene generation in situ and reaction with amines and imines, respectively, in good to excellent yields. The preferential formation of trans-configured β-lactams was observed during the [2+2] Staudinger cycloaddition of a range of ketenes with different imines under controlled reaction conditions. Some insights into the mechanism of this reaction at high temperature are reported, and a new web-based molecular viewer, which takes advantage from Augmented Reality (AR) technology, is also described for a faster interpretation of computed data.

N-Benzyl-2-[4-(trifluoromethyl)phenyl]acetamide (4a)

Yield: 65%; white solid; mp 134–136 °C.

1H NMR (600 MHz, CDCl3): δ = 7.61 (d, J = 8.05 Hz, 2 H), 7.41 (d, J = 8.00 Hz, 2 H), 7.32 (d, J = 7.53 Hz, 2 H), 7.28–7.34 (m overlapping d at 7.32 ppm, 1 H), 7.22 (d, J = 7.13 Hz, 2 H), 5.89 (br. s, 1 H), 4.43 (d, J = 5.8 Hz, 2 H), 3.64 (s, 2 H).

13C NMR (150.0 MHz, CDCl3): δ = 169.7, 138.8 (br s), 137.8, 129.6, 129.59 (q, J C–F = 32.5 Hz), 128.7, 127.62, 127.59, 125.8 (q, J C–F = 3.8 Hz), 124.0 (q, J C–F = 272.0 Hz), 43.8, 43.3.

IR (neat): 3238, 3063, 1625, 1556, 1328, 1122, 1070, 753, 698 cm–1.

HRMS: m/z [M + H]+ calcd for C15H15F3NO: 294.1100; found: 294.1090.

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