The total synthesis of c1'-azacycloalkyl hexahydrocannabinoids; the total synthesis of 3-oxaadamantyl hexahydrocannabinoids; the synthesis of bicyclic 3-adamantyl cannabinoids
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2014-12
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University of Hawaii at Manoa
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Chapter 1. A brief background on the discovery and pharmacology of cannabinoids and of cannabinoid receptors was described. Also, SAR and earlier synthesis approaches to tricyclic cannabinoids were reviewed. Chapter 2. The total synthesis of three series of C1'-azacycloalkyl 9β-hydroxy hexahydrocannabinoids: 2,2-disubstituted pyrrolidine, 3,3-disubstituted azetidine, and 2,2-disubstituted azetidine cannabinoids are described. The key steps in the synthesis for each series were the Liebeskind cross coupling, the Pd-catalyzed decarboxylative cross coupling, and the titanium enolate addition to Ellman's imine. 3,3-Disubstituted N-methyl azetidine and 2,2-disubstituted N-methyl pyrrolidine cannabinoids exhibited high binding affinities for CB1 and CB2 receptors that are similar to (-)-Δ9-THC while evaluation of binding affinities of 2,2-disubstituted azetidine cannabinoid is in progress. Chapter 3. The total synthesis of a series of 3'-functionalized 3-oxaadamantyl 9β-hydroxy hexahydrocannabinoids is described. The key steps in the synthesis were the nucleophilic addition of aryllithium to epoxide ketone to prepare an 3-oxaadamantyl resorcinol, condensation of resorcinol with a mixture of optically active diacetates followed by cyclization to construct the tricyclic cannabinoid nucleus, and functional group manipulation. It is noteworthy that no functional group protection was employed in the synthesis. Ligands with-CH2NCS and -CH2N3 as functional groups have affinities for CB1 and CB2 receptors at nanomolar or subnanomolar levels, and they can be used for LAPS studies in the group of Professor Makriyannis. Chapter 4. The synthesis of two series of cannabinoids: the bicyclic 3-adamantyl cannabinoids and the 3'-functionalized 3-oxaadamantyl 9β-hydroxymethyl hexahydrocannabinoids are described. In the synthesis of bicyclic 3-adamantyl cannabinoids, the challenging step, oxidation of bicyclic hydroxy isothiocyanate to bicyclic keto isothiocyanate, was accomplished with PDC with the preservation of the phenolic hydroxy groups. Evaluation of binding affinities for receptors of bicyclic cannabinoids are currently in progress. In the other series, the synthesis related to conversion of the 9-keto group to 9β-hydroxymethyl and 3'-functional groups. Ligands in this series with -CH2NCS and -CH2N3 have affinities for CB1 and CB2 at nanomolar and subnanomolar levels, and they are also used for LAPS studies.
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c1'-azacycloalkyl hexahydrocannabinoids
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Theses for the degree of Doctor of Philosophy (University of Hawaii at Manoa). Chemistry.
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