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

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

Cannabinoids

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…

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

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

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

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

Goal?

Dibenzofuran

PART II Optimization of Dibenzofuran Analogues

Reaction

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

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

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

Microwave Data Analysis

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

% Conversion Monitored by GC

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)

Synthesized Dibenzofuran Analogues

1HNMR of SA-104

PART III Conclusion, Future Work and Implications

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

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

Implications Synthesis of Rigid Analogues Cannabinoid Receptor Ligands

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

References

Questions ?