C1 C13 Research Articles

Synthesis of the C1–C13 Segment of Poecillastrin C

AbstractA stereoselective synthesis of the C1–C13 segment of poecillastrin C has been achieved. The C1–C4 moiety was derived from diallyl l-tartrate, and the amide group at the C3 position was constructed by means of a traceless Staudinger reaction. The C1–C13 segment was submitted to model studies, including esterification with a bulky alcohol at the C1 position and Stille coupling with vinyl iodide at the C13 position. The reactivity of the C1 position was affected by the neighboring C2-protective group. When the C2 hydroxy group was protected as a TBS ether, the C1 carboxylic acid did not undergo esterification with a bulky secondary alcohol, whereas the p-methoxybenzylidene N,O-acetal afforded a 2,4-dimethyl-3-pentyl ester. Stille coupling of the C1–C13 segment with 1-iodohept-1-ene gave the southern part of the poecillastrin C macrolactam attached to simplified eastern and western parts.

Bitumen fumes and PAHs in asphalt road paving: Emission characteristics, determinants of exposure and environmental impact

BackgroundAsphalt road paving and its subsequent complex airborne emissions have raised concerns about occupational exposures and environmental impacts. Although several studies described bitumen fumes or Polycyclic Aromatic Hydrocarbons (PAH) emissions at specific worksites, no comprehensive studies have characterised road paving emissions and identified the main determinants of exposure. MethodsA 10-year study from 2012 to 2022 was performed to examine the pollutants resulting from bitumen fume emissions and covering the main processes used in road paving (asphalt production, mechanical rolled asphalt paving, manual paving, mastic asphalt paving, emulsion paving, and coal-tar asphalt milling). A total of 623 air samples were collected at 63 worksites (on 290 workers, in the environment and near emission sources), and bitumen fumes, PAHs, aldehydes and volatile organic compounds were analysed. Biomonitoring campaigns were performed on 130 workers to assess internal exposure to PAHs. ResultsFume emissions revealed complex mixtures of C10–C30 compounds, including linear saturated hydrocarbons (C6–C12), alicyclic hydrocarbons and aliphatic ketones. PAHs were dominated by 2–3 aromatic ring compounds (naphthalene, fluorene, and phenanthrene), and C1–C13 aldehydes were identified. Binder proportion, paving temperature, outdoor temperature, workload and job category influenced airborne concentrations. A significant temporal trend was observed over the time period of the study, with decreasing BF and PAH exposures. PAH biomonitoring was consistent with air samples, and urinary metabolites of 2–3 ring PAHs dominated over 4–5 ring PAHs. Occupational exposures were generally far lower than exposure limits, except coal-tar asphalt milling activities. Very low environmental concentrations were measured, which highlights a negligible contribution of paving emissions to global environmental pollution. ConclusionThe present study confirmed the complex nature of bitumen fumes and characterised the main determinants of exposure. The results highlight the need to reduce the paving temperature and binder proportion. Recycled asphalt pavement use was not associated with higher emissions. The impact of paving activities on environmental airborne pollution was deemed negligible.

Synthesis of the C1–C13 Fragment of Eribulin

Key words eribulin - π-allyl rhodium complex - 6-endo-tet cyclization - vinyl epoxide

Synthesis of the C1–C13 Fragment of Eribulin on a Kilogram Scale

An improved kilogram-scale synthesis of the C1–C13 fragment of eribulin is disclosed. Rh-mediated 6-endo-tet cyclization of a vinyl epoxide provides a crystalline tetrahydropyran intermediate, which was transformed to a lactol intermediate having the bicyclic motif of the C3–C12 fragment. This intermediate was further elaborated into the C1–C13 fragment of eribulin following the precedent sequence of reactions.

Synthesis, anticancer activity, SAR and binding mode of interaction studies of substituted pentanoic acids: part II.

Aim: Our previous results suggest that phenyl/naphthylacetyl pentanoic acid derivatives may exhibit dual MMP-2 and HDAC8 inhibitory activities and show effective cytotoxic properties. Methodology: Here, 13new compounds (C1-C13) were synthesized and characterized. Along with these new compounds, 16 previously reported phenyl/napthylacetyl pentanoic acid derivatives (C14-C29) were biologically evaluated. Results: Compounds C6 and C27 showed good cytotoxicity against leukemia cell line Jurkat E6.1. The mechanisms of cytotoxicity of these compounds were confirmed by DNA deformation assay and reactive oxygen species assay. MMP-2 and HDAC8 expression assays suggested the dual inhibiting property of these two compounds. These findings were supported by results of molecular docking studies. In silico pharmacokinetic properties showed compounds C6 and C27 have high gastrointestinal absorption. Conclusion: This study highlights the action of phenyl/naphthylacetyl pentanoic acid derivatives as anticancer agents.

K2-HERMES II. Planet-candidate properties from K2 Campaigns 1-13

ABSTRACT Accurate and precise radius estimates of transiting exoplanets are critical for understanding their compositions and formation mechanisms. To know the planet, we must know the host star in as much detail as possible. We present complete results for planet-candidate hosts from the K2-HERMES survey, which uses the HERMES multi-object spectrograph on the Anglo-Australian Telescope to obtain $R\sim 28\, 000$ spectra for more than 30 000 K2 stars. We present complete host-star parameters and planet-candidate radii for 224 K2 candidate planets from C1–C13. Our results cast severe doubt on 30 K2 candidates, as we derive unphysically large radii, larger than 2RJup. This work highlights the importance of obtaining accurate, precise, and self-consistent stellar parameters for ongoing large planet search programs – something that will only become more important in the coming years, as TESS begins to deliver its own harvest of exoplanets.

Synthesis of the C1–C13 fragment of eribulin mesylate

Synthesis of the C1–C13 fragment of eribulin mesylate has been accomplished. It features a highly stereoselective construction of a trans-dihydropyran framework using three key reactions: (1) Sharpless epoxidation, (2) regioselective ring opening, and (3) olefin metathesis.

Sdrawkcab scitamehtam: The case for understanding mathematics backwards

Despite the widespread acknowledgement of the need for graduates with quantitative problem-solving skills, many students enter university having relied heavily on pattern recognition techniques for high school mathematics. While these can often lead students to obtaining correct solutions for problems similar to those which they have practised, they do not lead to a deeper understanding of the material and, critically, may not develop more widely-applicable skills. Even when correct solutions are obtained, students can sometimes not understand or explain why their solution is indeed correct. Here, I present an argument in favour of avoiding predictability in question structures and, in particular, asking questions ``backwards'' to how they might traditionally be asked. Some mathematical topics readily lend themselves to such approaches --- the Fundamental Theorem of Calculus tells us that an integral problem is inherently linked to an antiderivative problem --- whereas other require much more care and subtlety to avoid routine or predictable assessments. I will discuss some preliminary results from a first year probability subject at the University of Technology Sydney (UTS) which suggest that student understanding of material can be increased when they feel that prioritising pattern recognition over problem solving is unlikely to be rewarded with high marks. References Khan academy. expected value. URL: https://www.khanacademy.org/math/statistics-probability/random-variables-stats-library/random-variables-discrete/e/expected_value . Mark Asiala, Anne Brown, David J. Devries, Ed Dubinsky, David Mathews, and Karen Thomas. A framework for research and curriculum development in undergraduate mathematics education. Maa Notes, pages 37–54, 1997. I. Chubb. Science, technology, engineering and mathematics in the national interest: a strategic approach. Australian Government, Canberra, 7 2013. URL: http://www.chiefscientist.gov.au/2013/07/science-technology-engineering-and-mathematics-in-the-national-interest-a-strategic-approach/ . Ted Dunning. Accurate methods for the statistics of surprise and coincidence. Computational Linguistics, 19(1):61–74, 1993. Justin Kruger and David Dunning. Unskilled and unaware of it: How difficulties in recognizing one's own incompetence lead to inflated self-assessments. Journal of Personality and Social Psychology, 77(6):1121–1134, 1999. doi:10.1037/0022-3514.77.6.1121 . Fengshan Liu. 14 - teaching inverse problems in undergraduate level mathematics, modelling and applied mathematics courses. In Qi-Xiao Ye, Werner Blum, Ken Houston, and Qi-Yuan Jiang, editors, Mathematical Modelling in Education and Culture, pages 165–172. Woodhead Publishing, 2003. doi:10.1533/9780857099556.4.165 . David S. Moore, George P. McCabe, and Bruce A. Craig. Introduction to the Practice of Statistics. W. H. Freeman and Company, New York, 6th edition, 2009. Terezinha Nunes, Peter Bryant, Rossana Barros, and Kathy Sylva. The relative importance of two different mathematical abilities to mathematical achievement. British Journal of Educational Psychology, 82(1):136–156, 2012. doi:10.1111/j.2044-8279.2011.02033.x . L. J. Rylands and C. Coady. Performance of students with weak mathematics in first-year mathematics and science. International Journal of Mathematical Education in Science and Technology, 40(6):741–753, 2009. doi:10.1080/00207390902914130 . R. R. Sokal and F. J. Rohlf. Biometry: The Principles and Practice of Statistics in Biological Research. W. H. Freeman and Company, New York, 2nd edition, 1981. Arathi Sriprakash, Helen Proctor, and Betty Hu. Visible pedagogic work: parenting, private tutoring and educational advantage in australia. Discourse: Studies in the Cultural Politics of Education, 37(3):426–441, 2016. doi:10.1080/01596306.2015.1061976 . Jon R. Star. On the relationship between knowing and doing in procedural learning. In B. Fishman and S. O'Connor-Divelbiss, editors, Proceedings of fourth international conference of the Learning Sciences, pages 80–86. Erlbaum, 2000. S. Woodcock and S. Bush. Slipping between the cracks? maximising the effectiveness of prerequisite paths in uts mathematics degrees. In Mark Nelson, Tara Hamilton, Michael Jennings, and Judith Bunder, editors, Proceedings of the 11th Biennial Engineering Mathematics and Applications Conference, EMAC-2013, volume 55 of ANZIAM J., pages C297–C314, 8 2014. URL: http://journal.austms.org.au/ojs/index.php/ANZIAMJ/article/view/7943 . Stephen Woodcock. Development of enquiry-oriented learning in the mathematical sciences. In Mark Nelson, Dann Mallet, Brandon Pincombe, and Judith Bunder, editors, Proceedings of the 12th Biennial Engineering Mathematics and Applications Conference, EMAC-2015, volume 57 of ANZIAM J., pages C1–C13, 5 2016. URL: http://journal.austms.org.au/ojs/index.php/ANZIAMJ/article/view/10439 . F. P. Yee. Open-ended problems for higher-order thinking in mathematics. Teaching and Learning, 20(2):49–57, 2000. URL: https://repository.nie.edu.sg/handle/10497/365 .

Total Synthesis of Biselyngbyolide B and Its C21-C22 Z-Isomer.

Investigations toward the synthesis of the 18-membered macrolactone biselyngbyolide B (2) from a C1-C13 and a C14-C23 fragment are described. As a key reaction in the synthesis of the C1-C13 fragment, we used an asymmetric propargylation of chiral vinylketene silyl N, O-acetal 12. Access to a C14-C23 fragment featuring a skipped diene and a sensitive allyl alcohol function was initially attempted via reductive fragmentation of a pyran template. However, this ring opening on iodide 32 with t-BuLi led to dienynol 33 with a 21 Z double bond. With a silyl protecting group at 3-OH and by implementing an intramolecular Stille coupling for macrolactonization, the 21 Z-isomer of biselyngbyolide B (47) was obtained. For preparation of a C14-C23 fragment with the 21 E-configuration, a cross-coupling of vinylstannane 48 with 4-bromocrotonate (49) set the configuration of the two double bonds. Biselyngbyolide B (2) was then accessed by an intramolecular Heck coupling. In preliminary biological cytotoxicity assays, 2 turned out to be active, whereas the 21 Z-isomer 47 was much less active. The 3-OMEM analogue 40 was devoid of activity. These results support the notion that the side chain with the correct configuration is relevant for binding to the Ca2+-ATPase and the biological activity.

Stereoselective Synthesis of Northern Fragment of Eribulin Mesylate from d-Mannose

Stereoselective synthesis of northern fragment of eribulin mesylate is reported by coupling of the C1–C13 fragment with the C28–C35 fragment. The key steps involved in this synthesis are butyllithium-facilitated coupling between sulfone and aldehyde, then Dess–Martin periodinane oxidation followed by samarium(II) iodide mediated desulfonylation.

Toward a total synthesis of amphidinolide N: convergent synthesis of the C1–C13 segment

A convergent synthesis of the C1–C13 segment of amphidinolide N, a potent cytotoxic marine macrolide isolated from the dinoflagellate Amphidinium sp., was achieved. The key features of the synthesis involve vinylogous Mukaiyama and Evans aldol reactions to form the C1–C7 and C8–C13 fragments, and convergent union of the two fragments by means of an aldol reaction to construct the C1–C13 segment.

ChemInform Abstract: Gold‐Catalyzed Diastereoselective Synthesis of 2,6‐trans‐Disubstituted Tetrahydropyran Derivatives: Application for the Synthesis of the C1—C13 Fragment of Bistramide A (X) and B (XI).

ChemInform Abstract: Gold‐Catalyzed Diastereoselective Synthesis of 2,6‐trans‐Disubstituted Tetrahydropyran Derivatives: Application for the Synthesis of the C1—C13 Fragment of Bistramide A (X) and B (XI).

Total Synthesis of the 7,10‐Epimer of the Proposed Structure of Amphidinolide N, Part I: Synthesis of the C1–C13 Subunit

Amphidinolide N, the structure of which has been recently revised, is a 26-membered macrolide featuring allyl epoxide and tetrahydropyran moieties with 13 chiral centers. Due to its challenging structure and extraordinary potent cytotoxicity, amphidinolide N is a highly attractive target of total synthesis. During our total synthesis studies of the 7,10-epimer of the proposed structure of amphidinolide N, we have synthesized the C1-C13 subunit enantio- and diastereoselectively. Key reactions include an l-proline catalyzed enantioselective intramolecular aldol reaction, Evans aldol reaction, Sharpless asymmetric epoxidation and Tamao-Fleming oxidation. To aid late-stage manipulations, we also developed the 4-(N-benzyloxycarbonyl-N-methylamino)butyryl group as a novel ester protective group for the C9 alcohol.

Synthesis of the C1–C13 Fragment of Mandelalide A

This communication describes the synthesis of the fully functionalized C1 to C13 segment (southern part) of highly potent cytotoxic marine natural product mandelalide A. Pd-catalyzed oxa-­Michael cyclization followed by stereoselective reduction of the C7-ketone were carried out to construct the tetrahydropyran unit with required stereochemistry. The α,β-unsaturated ester moiety was constructed via cross-metathesis and the vinyl iodide was installed through modified Takai olefination.

Practical and stereoselective synthesis of [6,6,5]-tricyclic core (C1–C13) of eribulin mesylate

Fully functionalised [6,6,5]-tricyclic core (C1–C13) of eribulin is stereoselectively synthesized from d-mannose. This simple and practical approach involves Still and Gennari modification of HWE-reaction, Sharpless asymmetric dihydroxylation, and oxa-Micheal addition as key reactions.

Gold-catalyzed diastereoselective synthesis of 2,6-trans-disubstituted tetrahydropyran derivatives: application for the synthesis of the C1–C13 fragment of bistramide A and B

An efficient Au(iii)-catalyzed diastereoselective allylation leading to 2,6-trans-disubstituted tetrahydropyrans and application for the synthesis of the C1–C13 fragment of bistramide A and B is described.

ChemInform Abstract: Novel Iodine Catalyzed Diastereoselective Synthesis of trans‐2,6‐Disubstituted Tetrahydro‐2H‐pyrans: Synthesis of C1—C13 Fragment of Bistramide‐A.

AbstractTrans‐2,6‐substituted 2‐allylated pyrans are stereoselectively prepared by iodine catalyzed allylation of the corresponding tetrahydro‐2H‐pyranols.

Novel iodine catalyzed diastereoselective synthesis of trans-2,6-disubstituted tetrahydro-2H-pyrans: synthesis of C1–C13 fragment of bistramide-A

A new method for the stereoselective synthesis of trans 2.6-disubstituted tetrahydro-2H-pyrans has been developed involving iodine catalyzed allylation of tetrahydro-2H-pyranol with excellent trans selectivity. The method was also applied toward the construction of C1–C13 fragment of bistramide-A in 11 steps with 21.4% overall yield.

Tandem mass spectrometry (MSn) of peptide disulfide regio-isomers via collision-induced dissociation: Utility and limits in disulfide bond characterization

Mass spectrometric characterization of the disulfide connecting patterns directly from intact peptides and proteins is highly desirable but remains a challenging task. In this work, the regio-isomers of peptides containing two intrachain disulfide bonds were synthesized from P1 and P2 peptides (single letter sequence: C(1)ARIC(5)AKLC(9)LEVC(13)K and C(1)AEKC(5)IEKC(9)LVRC(13), respectively). They were further used as model systems to understand the fragmentation chemistry of each isomer under low energy collision-induced dissociation (CID) conditions. MS2 CID could easily identify the regio-isomer having a side-by-side disulfide linkage pattern (C1–C5 and C9–C13). However, the other two isomers with either loop-within-a-loop (C1–C13 and C5–C9) or overlapped disulfide configuration (C1–C9 and C5–C13) showed almost identical spectra and very limited sequence information could be obtained. Internal fragments which resulted from cleavages of two amide bonds from a sequence covered only by one disulfide loop were chosen for further dissociation. The MS3 CID data showed that certain internal fragment ions produced distinct fragmentation patterns which were useful in assigning the correct connecting pattern of the disulfide bonds for all three isomers. On the other hand, some internal fragment ions could undergo consecutive disulfide bond opening during collisional activation, which led to the observation of isomeric peaks from different disulfide regio-isomers. The latter situation made it difficult to independently assign the regio-isomers.

Commercial Manufacture of Halaven®: Chemoselective Transformations En Route to Structurally Complex Macrocyclic Ketones

The evolution of the synthesis of Halaven® (E7389, INN eribulin mesylate) from a medicinal chemistry process to the execution of the final process on pilot scale is described. The completion of the synthesis of Halaven® from C1–C13 ester and C14–C35 sulfone alcohol involves a series of chemo-, regio-, and stereoselective transformations. Furthermore, a high-dilution macrocyclization presented a number of challenges for industrial-scale manufacture (throughput, processing time, and side reactions). This paper describes studies at Eisai leading to an understanding, optimization, and control of the chemistry that realized the reproducible commercial production of Halaven®.