Diversity Oriented Synthesis of Benzopyran derived Natural Productlike Compounds

1
Diversity Oriented Synthesis of Benzopyran-
derived Natural Product-like Compounds
2nd Departmental Seminar University of Ottawa
Kamani Cumaranatunga-Ilangasinghe 20th March,
2003
2
Contents

• Introduction
• - Target oriented synthesis
• - Diversity oriented synthesis
• - Literature examples
• Project Outline
• Present Work
• Future Directions
• Conclusions

3
Introduction

• Target Oriented Synthesis
• - convergent approach
• - aimed at the total synthesis of natural
  products
• and analogs
• - methodology development
• - retrosynthetic analysis
• Diversity Oriented Synthesis
• - divergent approach
• - inspired by bioactive natural products
• - methodology development
• - structurally complex and diverse compounds
• - chemical probes for cell biology
• Schreiber, S. L., Chem. Eng News., 51-61 (March
  3, 2003)

4
Diversity Oriented Synthesis

• - Investigate new molecules that could
  exhibit
• biological responses
• - Complexity and diversity generating
  reactions
• Burke et al., Chem. Biol., 9,
  535-541 (2002)

5
Literature Examples

• 1. Focused, Natural Product Guided Approach
• 2. Biomimetic Approach
• 3. Natural Product-like Scaffolds

Arya, P. Baek, M.-G Natural Product-like, Chiral
Derivatives by Solid Phase Synthesis. Curr.
Opin. Chem. Biol. 5, 292-301 (2001)   Arya, P.
Joseph, R. Chou, D. T.-H. Toward
High-throughput Synthesis of Complex Natural
Product-like Compounds in the Genomics and
Proteomics Age. Chemistry Biology, 9, 145-156
(2002).
6
Focused, Natural Product Guided Approach
Waldmann et al., Angew. Chem. Int Ed., 38,
2904-2906, (1999)
7
Biomimetic Approach
Shair et al., J. Am. Chem. Soc., 121, 10648-49
(1999)
8
Protein Trafficking
9
Natural Product-like Scaffolds
Schreiber et al., J. Am. Chem. Soc., 121,
9073-9087, (1998)
10
Natural Product-like Scaffolds (contd.)
Arya, P. Chen, Z.-X Durieux, P. Joseph, R., J.
Am. Chem. Soc., (2003, submitted)
11
Goals and Expectations

• - Efficient access to diverse natural
  product-like, complex polycyclic derivatives
• - Useful chemical probes in understanding
  biological functions
• Tools
• - Methodology development (in solution)
• - Solid phase organic synthesis

12
Synthetic Targets
13
Project Outline

• Part 1 Stereoselective synthesis of benzopyran
  scaffold
• Part 2 Benzopyran-derived tricyclic derivatives
  having
• amino acid moiety
• Part 3 Benzopyran-derived tricyclic derivatives
  by ring
• closing metathesis
• Part 4 Solid phase organic synthesis
• Future directions
• Conclusions

14
Part 1 Benzopyran Scaffold
15
Scaffold Design
16
Literature Examples of Bioactive Plant
Polyphenolics
17
Model Studies
18
(No Transcript)
19
Part 2 Benzopyran-derived Tricyclic Derivatives
20
Synthetic Strategies
21
Mitsunobu
22
Leaving Group
23
Mitsunobu
24
Reductive Amination
25
Part 3 Ring Closing Metathesis Approach to
Tricyclic Derivatives
26
Six Membered Ring
27
NMR Six Membered Ring (trans-fused)
28
NMR Six Membered Ring (cis-fused)
29
Eight Membered Ring
30
Eight Membered Ring
Modeling
NOESY
31
Extensions In Solution Phase
32
(No Transcript)
33
Part 4 Solid Phase Organic Synthesis
34
Solid Phase Synthesis - General Aspects

• - Solid Supports
• Linkers
• Characterization/Analysis
• Parallel Synthesis
• Split Pool Synthesis
• IRORI Technology for Split Mix Like Synthesis

35
Advantages

• (1) Completion of Reaction
• - use of excess reagents
• (2) Purification and Isolation
• - by washing away excess reagents
• (3) Parallel Synthesis
• - rapid access to analogs
• (4) IRORI Radiofrequency Tagging Method

36
Immobilization for Solid Phase Synthesis
37
Solid Phase Synthesis
38
Extensions

• Manual Solid Phase Synthesis
• Modest Size Library Synthesis

39
Future Goals
40
Asymmetric Hetero-Michael
41
In Progress
42
Conclusions

• Successful in developing a novel method for
  the stereoselective synthesis of a benzopyran
  scaffold.
• Successful in synthesizing benzopyran-derived,
  tricyclic derivatives using RCM approach in
  solution phase.
• Demonstrated the possibility of transferring
  the RCM methodology onto solid phase synthesis.

43
Conclusions (contd.)
44
A Chemical Biology Approach to Understanding
Eukaryotic Protein Synthesisby Use of
Small-Molecules

• Prof. Jerry Pelletier
• Dept of Biochemistry
• McGill University
• Montreal

45
Two Main Information Pathways in the Cell
Transcription and Translation
46
Research Program to Interdict the Translation
Pathway

• Explore Strategies to Target Individual mRNAs
  Utilizing Small Molecules
• Inhibition of Translation with Small Molecule
  Ligands that bind mRNA
• Engagement of Protein/RNA Complexes by Small
  Molecule Ligands
• Identify Novel Inhibitors of Eukaryotic Protein
  Synthesis
• High-throughput Chemical Screening
• Bioinformatics

47
Rationale

• The translation cycle is very complex and small
  molecule ligands can provide insight into
  mechanistic details of this pathway.
• Deregulation of translation can be an initiator
  of oncogenesis.

48
Acknowledgements

• Dr. Prabhat Arya (Thesis Supervisor)
• Dr. Bugga Sarma (Post-doctoral Fellow)
• Dr. Majid Rastegar (Post-doctoral Fellow)
• Mike Barnes (Technical Officer)
• Donald Leek (NMR)
• Malgosia Daroszewska (MS-Electrospray)
• All past and present members of the group
• Department of Chemistry, University of Ottawa
• Financial Support
• NCIC
• NRC Genomics Program

49
Future Studies (contd.),
50
NMR Eight Membered Ring
COSY