Browsing by Subject "Total Synthesis"
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Item I. synthesis, reactivity, structure and application of spiroepoxy-b-lactones: studies toward (-)-maculalactone a ii. metal mediated couplings of dichloroolefins applicable to the haterumalides(2009-05-15) Duffy, Richard JeffreyMarine natural products have continued to be a source of compounds with interesting structures and biological activities. Two such compounds are maculalactone A and haterumalide NA. In the process of exploring a route to the synthesis of haterumalide NA, the novel ring system, spiroepoxy-b-lactones were discovered. Spiroepoxy-b-lactones were synthesized by the oxidation of ketene-homo dimers with dimethyldioxirane (DMDO). After a synthetic route to this ring system was obtained we next explored the varied reactivity of spiroepoxy-b-lactones, and it was apparent that they might be applied to the synthesis of maculalactone A. Also with the aim of the total synthesis of the haterumalides, a palladium catalyzed cross coupling was developed. This reaction couples a 1,1-dichloroolefin with an alkyl zinc reagent. It was found that this reaction necessitates a heteroatom on the zinc reagent in order to proceed.Item Synthetic Studies of Iriomoteolide-1A Total Synthesis of Alotaketal A and an Antifungal O-Hydroxy-P-Quinone Methide Diterpenoid(2013-11-07) Huang, JinhuaNatural products are a rich source of compounds with interesting structures and biological activities. Three bioactive natural products, iriomoteolide-1a, alotaketal A, and an unnamed quinone methide diterpenoid, attracted our attention during our course of exploring natural products as potential leads for biomedical discovery. The structure of iriomoteolide-1a had been misassigned, but the potent cytotoxicity reported for this natural product warranted further studies to elucidate its true structure. As part of our effort toward this goal, we finished the total synthesis of a diastereomer of iriomoteolide-1a. Our total synthesis featured a lithium acetylide-chloroformate coupling to assemble the alkyne and chloroformate fragments, the ring closing metathesis to exclusively generate the 15E-macrocyclic diolide, and a SmI_(2)-mediated intramolecular reductive allylation to form the cyclic hemiketal. The bioactivities of this diastereomer were evaluated, but only weak inhibition of cell proliferation was observed at 10 ?M toward HeLa and PC3 cell lines. Alotaketal A was reported to potently (EC_(50) = 18 nM) activate the cAMP (cyclic adenosine monophosphate) signaling pathway in HEK293 cells transformed with the pHTS-CRE plasmid. Our synthetic efforts toward this natural product culminated in the first enantioselective total synthesis of (-)-alotaketal A. Our total synthesis employed both intra- and inter-molecular reductive allylation of esters for assembling the bicyclic lactone and coupling the fragments. A Hg(OAc)_(2)-mediated allylic mercuration was used to introduce the C22-hydroxyl group. The subtle in?uence of substituents over the course of the spiroketalization process was revealed. The synthesis con?rmed the relative and absolute stereochemistry of (-)-alotaketal A and allowed veri?cation of alotaketal A?s e?ect over cAMP signaling using reporter-based FRET imaging assays with HEK293 cells. Our studies also revealed alotaketal A?s unique activity in selectively targeting nuclear PKA signaling in living cells. Our synthetic efforts toward the unnamed quinone methide diterpenoid 1.67 led to the first total synthesis of this potent antifungal product (MIC = 0.19 ?M). Our total synthesis was highlighted by a Stille coupling to introduce the allyl group, a lithium/naphthalene-mediated coupling reaction for fragment assembling, and a BBr3-mediated one-pot bis-demethylation and intramolecular Friedel-Crafts alkylation to build the tricyclic molecular framework. Our preliminary structure-activity relationship study showed that the 2'-hydroxyethyl side chain of the natural product was nonessential to its antifungal activity.Item The Transannular bis-Michael Reaction in the Synthetic Studies of Celastrol and the Development of Novel Palladium-Catalyzed Reactions(2013-11-11) Kaiser, Thomas MaxwellPharmaceutical R&D is currently undergoing a productivity crisis. Also, the loss of activity of established medicines continues to reduce the pool of agents capable of treating infectious diseases. Small molecule synthesis and synthetic methodology development continue to be essential scientific endeavors due to the ability of synthetic chemistry to create new starting points for the development of medicines. Therefore, in order to increase the ability to discover new medicines, more efficient synthetic strategies and transformations capable of generating structurally complex drug-like molecules are required. This work explored the transannular bis-Michael reaction (TMR) as a potential method to access polycyclic natural products in an efficient manner. We sought to develop an expedient route to an all-carbon Z,E macrocyclic precursor to the TMR and we then evaluated whether the Z,E isomer would follow our proposed model for the TMR. Our strategy relied on a 1,3-dipolar cycloaddition to access the TMR precursor. However, this 1,3-dipolar synthetic route had a low synthetic efficiency. Consistent with our other studies, this Z,E-macrocyclic bis-enone was found to be inactive in the transannular bis-Michael reaction cascade for the conditions evaluated. En route, we also discovered that our 1,3-dipolar cycloaddition gave a rare 3,4-disubstituted isoxazole under kinetic reaction conditions. We also demonstrated that the dipolar cycloaddition is reversible and the thermodynamic 3,5-disubstituted isoxazole can be obtained through isomerization of its 3,4-disubstituted isomer under elevated temperature. Our initial mechanistic studies support the role of hydrogen-bonding in accelerating the isomerization process. Our work in developing new palladium-catalyzed reactions resulted in a novel palladium-catalyzed enamine Heck reaction. This reaction is capable of generating ?,?-unsaturated ketones directly from aldehydes and vinyl iodides. However, the limitations of scope in both vinyl iodide and aldehyde severely limit the synthetic utility of the reaction described herein. Also, our work clearly demonstrated a novel enantioconvergent approach to 3-allyl-3-alykl-indolenines through the use of a chiral palladium/trialkylborane dual catalyst system. We suggest a greater role of trialkyl borane beyond allylic alcohol activation in previous allylation examples employing R_(3)B/allyl alcohol as the allyl source. Finally, we extended or understanding of the role of Et_(3)B to the Tamaru allylation. The Lewis acid, Et3B, facilitates enolization and behaves as a co-catalyst to effect the allylation of aldehydes. We have also begun developing an enantioselective version of this reaction that suffers from low enantioselectivity. This reaction was shown to be selective for aldehydes as ketones did not react under the described conditions.Item Total synthesis of (–)-dihydroprotolichesterinic acid via a diastereoselective conjugate addition, development of enantioselective halocyclization reactions, and progress towards the total synthesis of jiadifenolide(2015-12) Hethcox, John Caleb; Martin, Stephen F.; Krische, Michael J; Dong, Guangbin; Holliday, Bradley J; Kerwin, Sean MIn an effort to develop a unified route to functionalized succinic acid derivatives, a new diastereoselective conjugate addition of monoorganocuprates, Li[RCuI], to a chiral fumarate was developed. The conjugate addition proceeded with good yields and a high degree of diastereoselectivity for a variety of alkyl and aryl nucleophiles. Application of this new methodology culminated in the shortest total synthesis of (–)-dihydroprotolichisterenic acid to date. The novel organocatalyst developed by the Martin group was applied to enantioselective iodolactonization reactions. Reaction conditions were optimized and the resulting halolactones were obtained in high yields and enantioselectivities for a number of olefinic acids. Of particular note is the disclosure of the first iodolactonization reactions forming a C–I bond at a stereogenic center. The utility of this catalyst was further extended to kinetic resolution reactions. Additionally, this catalyst was found to promote the first enantioselective halolactamization reaction with moderate enantioselectivity. Finally, the catalyst was modified in an effort to enhance the enantioselectivity and verify the proposed bifunctional nature of the catalyst. Lastly, an enantiospecific total synthesis of the neurotrophic sesquiterpenoid natural product (–)-jiadifenolide was progressed. The stereochemistry was introduced by the use of commercially available (+)-pulegone as the starting material. The first diastereoselective decarboxylative allylation on a cyclopentanone was developed A samarium diiodide mediated radical annulation was planned to forge two of the rings, and late stage oxidation manipulation could then lead to the completion of the synthesis.