Synthesis of Discodermolides Useful for Investigating Microtubule Binding and Stabilization Melissa G. Morris CHEM 635 February 12, 2013 Hung, D. T.; Nerenberg,

Slides:

Advertisements

Similar presentations

Ms. Hirsh Physical Science

Advertisements

Formal Total Synthesis of (+/-)-α- and β- Cedrene by Preparation of Cedrone. Construction of the Tricyclic Carbon Skeleton by the Use of a Highly Efficient.

Total Synthesis of BE-43472B. PhD Work with Prof. André B. Charette.

Total Synthesis of Prostaglandins F 2α and E 2 as the naturally occurring forms Kirk W. Shimkin Total Synthesis Spring 2012 Corey, et al. JACS, 1970, 92,

Stereocontrolled Total Synthesis of (+)-Vinblastine Satoshi Yokoshima, Toshihiro Ueda, Satoshi Kobayashi, Ayato Sato, Takeshi Kuboyama, Hidetoshi Tokuyama,

Synthesis of Vancomycin from the Aglycon Christopher Thompson, Min Ge, Daniel Kahne J. Am. Chem. Soc. 1999, 121, Presented by James Melnyk.

Total Synthesis of (±)-Longifolene Yiyun Peng March 4th, 2013 W. Oppolzer, T. Godel, J. Am. Chem. Soc. 1978, 100, 2583 – 2584.

Lecture #4 Chemical Reactions. Basic Properties of Chemical Reactions Stoichiometry -- chemistry Relative rates – thermodynamics; K eq = f(P,T) Absolute.

Amos B. Smith Mounuo Cheng Prof. Amos B. Smith Rhodes-Thompson Professor of Chemistry University of Pennsylvania, Amos B. Smith, III (born August.

1 D. A. Evans’ Asymmetric Synthesis — From 80’s Chiral Auxiliary to 90’s Copper Complexes and Their Applications in Total Synthesis Supervisor: Professor.

Total Synthesis and Evaluation of [ψ[CH 2 NH]Tpg 4 ] Vancomycin Aglycon: Reengineering Vancomycin for Dual D -Ala- D - Ala and D -Ala- D -Lac Binding Brendan.

A 1 A 2 A 3 A 4 B B B

Alkylation by Asymmetric Phase- Transfer Catalysis 张文全.

WORKSHOP (1) Presented by: Afsaneh Bazgir Polymerase Chain Reaction

Organic Synthesis A synthesis is a specific sequence of chemical reactions that converts starting materials into the desired compound, called the target.

Ingólfur Magnússon 12. May 2014

Molecular things you want Molecular things you have ? chemists.

Lactacystin: An Inhibitor in the Ubiquitin Proteasome Pathway Ami Jun-Yee Chin February 17, 2005.

Click chemistry for synthesis of chitosan nanocarriers and biomaterials Ingólfur Magnússon 17th. June 2014.

Further Attempts Towards the Synthesis of Benzo-Annelated Cross-Bridged Cyclam Synthesis of Cross-Bridged Benzocyclam The Department of Chemistry of the.

Florida Department of Education Bureau of School Improvement Office of Curriculum Support.

1 BE : An Inhibitor of DNA –Topoisomerase II Indira Thapa November 24, 2005.

Jin Kim Montclare Polytechnic Institute of NYU Department of Chemical and Biological Sciences March 22, 2010 Engineered Protein Biomaterials.

Enantioselective Total Syntheses of Manzamine A and Related Alkaloids John M. Humphrey, Yusheng Liao, Amjad Ali, Tobias Rein, Yue-Ling Wong, Hui-Ju Chen,

The Mode of Action and Possible Target of Artemisinin

Total Synthesis of (+)-Discodermolide CHEM635 Kelsey Roberts Group B February 19, 2013 Patterson, I*; Florence, G. J.; Gerlach, K.; Scott, J. P. Agnew.

Total synthesis of 6-Deoxyerethronolide B CHEM 635 Kelsey Roberts 05/07/13 Gao, X.; Woo, S.K.; Krische M.J. J. Am. Chem. Soc. 2013, 135, 4223.

Catalytic Asymmetric Total Syntheses of Quinine and Quinidine Izzat T. Raheem, Steven N. Goodman, and Eric N. Jacobsen J. Am. Chem. Soc. 2004, 126, 3,

Nucleosome structure. Histones Most of the protein in eukaryotic chromatin consists of histones, of which there are five families, or classes: H2A, H2B,

Kang Hyun Jung. Introduction Leucascandrolide A (1, Scheme 1) was isolated in 1996 from the calcareous sponge Leucascandra caveolata, collected off the.

A Cycloaddition Cascade Approach to the Total Synthesis of (-)-FR David A. Evans and JeremyT.Starr Presented by Vijayarajan Devannah 2/19/2013.

-1- The Chemistry and Biology of Discodermolide Yueheng Jiang November 20, 2003.

Introduction. Zn 2+ homeostasis is regulated at the transcriptional level by the DNA-binding protein SmtB. Manipulation of Zn 2+ homeostasis could act.

1 Convergent Synthesis of Alternating Fluorene-p-xylene Oligomers and Delineation of the (Silver) Cation- Induced Folding Vincent J. Chebny and Rajendra.

Identification of the diterpene synthase in Salvia divinorum used to synthesize salvinorin A Adrian Laurenzi Tucson High Magnet School Research Methods.

Chemistry XXI Unit 2 How do we determine structure? M4. Inferring Charge Distribution Analyzing the distribution of electrons in molecules. M3. Predicting.

OSU Faculty Research Presentation Professor Michael Lerner Oct 14, 2011.

Synthesis of Leucascandrolide A via a Spontaneous Macrolactolization J. Am. Chem. Soc. 2002, 124, Presented by Vijayarajan Devannah 3/19/2013.

The total synthesis of (-)-cyanthiwigin F by means of double catalytic enantioselective alkylation J.A. Enquist, Jr., B.M. Stoltz, Nature 2008,453,1228.

Asymmetric Total Synthesis of Caribenol A Author: Zhen Yang J. Am. Chem. Soc. 2010, 132, Presented by Daniel Roberts April 6 th 2014.

Erik J. Sorensen B.A. in Chemistry from Syracuse University (1989)

Peter Yates ( ) B.Sc from the University of London, 1946.

Biomimetic Synthesis and Structural Revision of (+/-)-Tridachiahydropyrone P. Sharma, N. Gri ﬃ ths, J. E. Moses, Org. Lett. 2008, 10, 4025 – 4027 Present.

Synthesis Making molecules you want from the ones you have.

Total Syntheses of Di- and Tri-O-methyl Dynemicin A Methyl Esters Jack Taunton, John L. Wood, and Stuart L. Schreiber Department of Chemistry, Harvard.

3D model of Vindoline.

A Synthesis of (+)-FR182877, Featuring Tandem Transannular Diels-Alder Reactions Inspired by a Postulated Biogenesis David A. Vosburg, Christopher D. Vanderwal,

Michael J. Krische B.S.in Chemistry from University of California at Berkeley (1989) Fulbright Fellow at Helsinki University (1990) Ph.D. in Chemistry.

Rychnovsky’s Formal Synthesis of Leucascandrolide A Presented by BriAnne Bentivegna March 19, 2013 University of Delaware Kopecky, D.J.; Rychnovsky, S.D.

Progress towards the Synthesis of 1-Benzoxepin; A Model Oxepin Substrate Ian Smith, Ryan Fitzgerald, Holly Guevara, Arthur Greenberg

Access to the Akuammiline Family of Alkaloids : Total Synthesis of (+)-Scholarisine A Speaker ： Yi-Chih Lu Date ： 2013/4/20 Gregory L. Adams, Patrick J.

Prokaryotic Transcription Eukaryotic Transcription Both.

Combinatorial Chemistry

Total Synthesis of Manzamine A and Related Alkaloids

Zhengren Xu, Qian Wang, and Jieping Zhu*

Low-Valent Iron-Catalyzed Transformations of Unsaturated Hydrocarbons

Cocoa extract inhibits in vitro α-glucosidase activity:

Total Synthesis of the Potent cAMP Signaling Agonist (–)-Alotaketal A

DNA Replication.

HONORS AND AWARDS 时间： :30 地点：礼东二楼报告厅 TITLE

Academic Lecture Rational Synthesis and Assembly of Nanocatalysts for Energy Applications 报告人：Prof. Shouheng Sun (Brown University,美国布朗大学) 时间：

In situ & Ex situ Characterization of Nanocrystals

Total Synthesis of Leucascandrolide A

Martin D Burke, Gojko Lalic Chemistry & Biology

Electropolymerizable Dendrons in Reversible Addition Fragmentation Chain-Transfer (RAFT) Polymerizations: Electrochemical Behavior and Macromolecular Assemblies.

Total Synthesis of Epothilone A: The Olefin Metathesis Approach

Enantioselective, Palladium-Catalyzed α-Arylation of N-Boc-pyrrolidine

Biosynthetic phage display: a novel protein engineering tool combining chemical and genetic diversity Mary A Dwyer, Wuyuan Lu, John J Dwyer, Anthony.

Kirk W. Shimkin Total Synthesis Spring 2012

Yields from Varying Lab Sections Summary and Conclusions

Presentation transcript:

Synthesis of Discodermolides Useful for Investigating Microtubule Binding and Stabilization Melissa G. Morris CHEM 635 February 12, 2013 Hung, D. T.; Nerenberg, J. B.; Schreiber, S. L. J. Am. Chem. Soc. 1996, 118,

Stuart L. Schreiber, Ph.D. Born February 6, 1956 B.A. in chemistry from UVA, 1977 Ph.D. from Harvard University Joined Yale University faculty in 1981  Promoted to associate professor in 1984  Full Professor in 1986 Retuned to Harvard in 1988–present  Morris Loeb Professor of Chemistry and Biology  Director of Chemistry Biology  A Founding Member of the Broad Institute of Harvard and MIT. His research is focused in chemical biology >460 publications

History  1990–isolated by Gunasekera and co-workers at the Harbor Branch Oceranographic Institute from the deep-sea marine sponge Discodermolide dissoluta  1993–Schreiber and co-workers reported the first total synthesis of Discodermolide, but unfortunately the unantural antipode, (-)- Discodermolide  They also determined the absolute stereochemistry, something Gunasekera was unable to determine

Retro-synthesis 2 = C-C 7 3 = C 9 -C 15 4 = C 16- C 24

Forward Synthesis Synthesis of C1-C7 Synthesis of C9-C15

Forward Synthesis Cont. Synthesis of C16-C24

Combining the Fragments Reduction of acetylene was too problematic in the presence of the terminal diene C16-C24 C9-C15

Revision of Coupling

…doesn’t work! The Final Step…

Final Step Revised

Stereochemistry  His original total synthesize provided: ([  ] 20 D = -13.0(c = 0.6, methanol)).  The current synthesis provided: ([  ] 20 D = (C = 0.6, methanol)), which was obtained via biological characterization

Synthesizing Derivatives for Biological Studies  Purpose: To further characterize the interactions between Discodermolide and its receptor  How : Synthesize an array of targets that can be analyzed when subjected in vivo  Why: Disocdermolide comprises numerous biological properties:  Immunisuppressive  Antiproliferative/antimitotic  Potent microtubule-stabilizing agent

Structural Variants for Studying Interactions with Discodermolide Receptor Before these variants were made, truncated version of Discodermolide were tested to see if the full length is needed for receptor recognition

Structural Variants Cont.  32 and 35 were not active in vivo, suggesting that the full length of Discodermolide was necessary for receptor recognition

Binding Reagent Syntheses

Binding Reagents Cont.

SubstrateProductR1R1 R2R2 IC 50 27b 50a  PhS S-Me6nM 27a 50b  PhS S-Me4nM 26b 51  PhS H4nM

Summary of Reagents and Activities no.IC 50 a (nM)no.IC 50 a (nM) 11a c a6 41b1150b Final Biological Assay Results

Conclusion  A total synthesis of (+)-Discodermolide in 36 steps, with an overal yield of 4.3% over 24 steps (the longest linear sequence)  Discodermolide remains the most potent natural promoter of tubulin assembly

(Extra) Synthesis of 59