Browsing by Subject "Total synthesis"

Now showing 1 - 4 of 4
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    Design and synthesis of tubulysin analogs that stabilize and mimic a key acetate important for potent antiproliferative activity against multi-drug resistant cancers
    (2012-10) Peterson, Michael Thomas
    Tubulysins are antimitotic natural products with potent anticancer activity against multidrug-resistant (MDR) cancer cells, acting by inhibition of tubulin polymerization. The marked difference in antiproliferative activity between tubulysins V and U exemplifies the importance of an acetate positioned alpha to the thiazole ring. However, this acetate has been shown to be labile under both acidic and basic conditions, so the effectiveness of this modification may be hindered due to this instability. Hence, the work presented here focuses on the synthesis of analogs that mimic and stabilize the acetate at this position.Heteroatom exchange at the α-thiazole position of tubuvaline was hypothesized to increase molecular stability while maintaining observed activity by bioisosteric replacement of the tubuvaline oxygen with a nitrogen. The nitrogen-containing analogs of tubulysin V and U, N tubulysin V and U, were the most important targets to test the singular modification of heteroatom exchange on bioactivity and to survey molecular stability. The synthetically derived N tubuvaline amino acid residue was generated following a rigorously controlled Mitsunobu reaction, but difficult final stage deprotections to N tubulysin V suggests a lowered stability compared to tubulysin V. N-acylation of a penultimate tetrapeptide intermediate led to generation of N tubulysin U and other acylated N tubulysin analogs to establish a more robust SAR at the α-thiazole position. N Tubulysin U was found to be more stable than tubulysin U under strongly basic conditions, and upcoming biochemical evaluation will determine the effect that these modifications have on antiproliferative activity.Investigations into the SAR at the tubuvaline α-thiazole position also included oxygen-based analogs, where two methods for acylation of tubulysin V were exploited to generate O-acylated analogs with various alkyl groups. Biochemical evaluation of antiproliferative activity, along with the use of two electrophilic analogs to act as affinity labels, will survey important interactions within the tubulysin-tubulin binding site.
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    Strategies for the synthesis of bioactive compounds: biomimetic approaches to the Salinosporamides and the hexadehydro-Diels-Alder reaction
    (2013-08) Willoughby, Patrick
    Part I: The salinosporamides are a subset of polyketide-derived marine natural products that have as their key structural feature a fused γ-lactam/β-lactone moiety. These molecules are known to inhibit the 20S proteasome (20SP) by utilizing the β-lactone reactivity, a promising target for cancer therapeutics. We propose that salinosporamide A may be formed biosynthetically by a non-enzymatic bis-cyclization event involving an uncatalyzed intramolecular ketene-ketone [2+2] cycloaddition of an amidoketene precursor. We also propose a transition state that places the C2 substituent pseudo-equatorial, allowing for enhanced stereoselectivity during bis-cyclization. Enolate formation from a thioester followed by internal acylation and concurrent loss of thiolate would form a 5(4H)-oxazolone. It is known that 5(4H)-oxazolones readily tautomerize to 4-hydroxyoxazoles, which are in equilibrium with their mesoionic Münchnone forms. Valence bond isomerism interconverts Münchnones to amidoketenes. Spontaneous ketene-ketone [2+2] cycloaddition would siphon the precursors through such a tautomeric manifold to give the natural product. Progress toward the synthesis of the biosynthetic precursors to salinosporamide A is disclosed in Chapters 3-5.Part II: The second part of this Thesis describes our recent, serendipitous encounter with the hexadehydro-Diels-Alder (HDDA) reaction. The HDDA reaction is a mode of the Diels-Alder reaction that involves [4+2] cycloaddition between a diyne and an alkyne to form aryne reactive intermediate. In Part II we show the scope of substrates that are capable of generating an aryne via the HDDA reaction. Additionally, we show that HDDA-mediated generation of arynes allows for the discovery of new modes of aryne trapping, for example, the desaturation of hydrocarbons.
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    Studies toward the total synthesis of rac-Leuconolam, modified Julia Olefination approach to access functionalized steroidal side chains, proton-NMR Studies of Mosher-like esters, and exploring a non-enzymatic Diels Alder reaction to account for the methyl sarcophytoate core
    (2012-09) Izgu, Enver Cagri
    This Ph.D. thesis is composed of five chapters, two of which are closely related and are presented at the begining. In Chapter-I, an extensive study toward the total synthesis of a plant natural product, namely leuconolam, will be discussed. In the course of this project, two different routes have been explored, where novel synthetic methods have been developed. In particular, some of the key bond-forming events such as Ireland-Claisen rearrangement, arene-alkene coupling (via either Stille reaction or C-H bond functionlization) and allylative ring closure are highlighted.A side project that has emerged during my investigations in Chapter-I will be covered in Chapter-II. This work focuses on the synthesis of two new organometallic reagents and their utility in organopalladium mediated cross-couling reactions with various alkenyl and aryl halides. Chapter-III encompasses the studies in the area of steroid chemistry, more specifically, in chemical construction of important steroid side chains. In order for a convergent strategy, a modified Julia olefination method has been performed on a common sulfone donor with a series of uselful aldehyde acceptors. Biologically relevant derivatives of alkyl and alkoxy branched side chains have been successfully synthesized. In Chapter-IV, synthetic and spectroscopic studies in Mosher ester analysis technique will be discussed. This NMR based tool is critical in determining the absolute configuration of a stereogenic carbon center and is commonly used by organic chemists. Finally, in Chapter-V, our efforts in generating a reactive pyrylium dienophile to facilitate a Diels-Alder reaction will be outlined.
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    Toward a total synthesis of Englerin A
    (2014-12) Goebel, Erik S.
    Englerin A is a guiane sesquiterpenoid isolated from the spurred potato-bush Phyllanthus engleri that has shown potent and selective activity against renal cancer cell lines. Our approach to the synthesis of englerin A features a Diels-Alder reaction between an axially chiral allene and a 3-siloxyfuran. We have found the oxabicyclo[2.2.1]heptane framework to be a sterically formidable structure and have discovered a novel decomposition pathway of acetyl-oxabicyclo[2.2.1]heptanes to 3(2H)-furanones.