1. Synthesis of Dibenzofuran Analogues
Sadia Akram
Advisor: Mark L. Trudell
UL Academic Summit 2013
04/13/2013

2. Outline of presentation
Part I – Introduction to Cannabinoids and Synthesis of Diaryl Either
A brief history of cannabinoid research
Part II-Optimization of Dibenzofuran Analogues
Synthesis
Part III – Conclusion
Future work and Implication

3. Cannabinoids

4. Δ9-tetrahydrocannabinol
Primary psychoactive component in cannabis
Many related molecules found in plant are also pharmacologically significant
Has been consumed medicinally and recreationally by humans for thousands of years
Physiological effects include:
Appetite stimulation, analgesia, euphoria, fatigue, anxiety…

5. But how? Magic? Nonspecific interaction with membrane?
Binding to a specific receptor?

6. Binding to a Specific Receptor
Two cannabinoid receptors have been classified to date
CB1 (brain)
CB2 (immune system)

7. Background Research Diaryl Ether BAY59-3704 Partial Agonist
Equal binding affinity to CB1 and CB2 receptors
No withdrawal behavior
No abuse potential
Potential target to explore SARs

8. Synthesis of Diaryl Ethers
X = CN
Y = CF3
Z = H
R1 = H
R2 = C6 H13
Ki = 1.2 nM

9. Goal?

10. Dibenzofuran

11. PART II Optimization of Dibenzofuran Analogues

12. Reaction

13. Various Conditions CATALYST SOLVENT BASE Oxygen Source Additive
Pd (OAc)2
Pivalic Acid
K2 CO3 O2
IMes
Pd (Cl)2
Pivalic Acid + EtOH
Benzoquinone
Rh2 (OAc)4
(dimmer)
EtOH

14. Initial Reaction Trials Data
Entry
AMS
115
Catalyst
Pd (OAc)2
Base
K2CO3
Solvent
Pivalic Acid O2
Source
Temp
Time
Conv.
mmol
mol% gm oC
hrs %
SA-97
0.5 5 10
0.45 -
120 72 17
SA-98
EtOH (0.2ml) 81 31
SA-99
<1
SA-100
EtOH (4ml)
120 (reflux)
SA-101
SA-102 20
0.9
SA-104 25
1.1
SA-106 (V)
2.0 39
SA-107
20 Pd(Cl)2
1.0
SA-111
(V)
2.1
25 x 3
1.0 x 3
12 (days) 66

15. Microwave Reaction Trials
Entry
AMS
115
Catalyst
Pd (OAc)2
Base
K2CO3
Solvent
Pivalic Acid O2
Source T
Time
Conv.
mmol
mol% gm oC
hrs %
SA-115
0.5
25 x 3 25
1.0 x 3
H2O2
(2.2 mmol)
120 5 19
SA-117
25 x 2 -
110 2
SA-123
100
4.0
150
SA-124
2.5 6

16. Microwave Data Analysis

17. More Reaction Data AMS 115 Catalyst Pd (OAc)2 Base K2CO3 Solvent
Entry
AMS
115
Catalyst
Pd (OAc)2
Base
K2CO3
Solvent
Pivalic Acid
Temp
Time
Conv.
mmol
mol% gm oC
hrs %
SA-126
0.5 25
1.1
120
144 82
SA-127 (RBF reflux) 63
SA-128
160 44
SA-129
25 + IMes (50 mol%)
2.0 49 7
SA-131
Rh2(OAc)4 24 3

18. % Conversion Monitored by GC

19. Synthesis of Dibenzofuran Analogues
Entry
(mmol)
Catalyst
Pd (OAc)2
(mol%)
Base
K2CO3
Solvent
Pivalic Acid
(g) O2
Source
Temp
(oC)
Time
(h)
Conv.
(%)
SA-126
0.5 25
1.1
air
120
144 82
SA-132
1.2 20 97
SA-135 40
SA-129 IM
SA-140
1.,2
IM = intractable material (this means that no single product could be isolated)

20. Synthesized Dibenzofuran Analogues

21. 1HNMR of SA-104

22. PART III Conclusion, Future Work and Implications

23. Conclusion Reaction is very slow
Solvent and catalyst amounts are crucial
Surface area
Temperature
Electron-withdrawing groups favor ring closure

24. Future Research Effort to purify the product
Synthesis of several other dibenzofuran analogues

26. Implications
Synthesis of Rigid Analogues Cannabinoid Receptor Ligands

27. Acknowledgment
Special thanks to Dr. Mark Trudell and Alexander Sherwood
Dr. Matthew Tarr and Phoebe Ray
Other graduate and undergraduate students
COSURP, University of New Orleans

28. References

29. Questions ?