Browsing by Subject "Alkaloids--Synthesis"
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Item Formal syntheses of hirsutine and rhynchophylline and progress toward the enantioselective total synthesis of citrinadin A(2007-05) Pettersson, Martin Youngjin, 1974-; Martin, Stephen F.The diastereoselective formal syntheses of the corynanthe alkaloid hirsutine and oxindole alkaloid rhynchophylline are described. The general approach features the use of ring-closing metathesis (RCM) to construct an [alpha],[beta]-unsaturated lactam, which is subjected to 1,4-addition. The lithium enolate of ethyl-1,3-dithiolane-2-carboxylate was identified as the optimal nucleophile in these systems. A key feature of this approach is that the stereochemical outcome of the 1,4-addition can be effectively controlled by appropriately sequencing the indole Boc-protection step to give either the C(3)-H/C(15)-H cis or C(3)-H/C(15)-H trans stereochemical relationship. As a result, we have developed a unified approach to both the "normal" and "pseudo" corynanthe alkaloids. This finding was highlighted through the synthesis of the complete carbon skeleton of the archetypal normal corynanthe alkaloid dihydrocorynantheol. An efficient synthesis of the tricyclic spiroindolinone ABC-fragment of the marine alkaloid citrinadin A has been achieved. The synthesis relies on a novel asymmetric oxidative rearrangement of an indole to an oxindole using a chiral auxiliary on the indole nitrogen to achieve facial selectivity. The transformation proceeds via the epoxidation of the indole C(2),C(3) double bond using DMDO, followed by a silica gelmediated 1,2-epoxide rearrangement. Using this tactic, the spirooxindole of citrinadin A, which contains two adjacent quaternary centers, was formed in high yield and excellent diastereoselectivity. Efforts toward the fragment coupling of the tricyclic spiroindolinone with a 2,4,6-trisubstituted piperidine coupling partner are described.Item Studies directed toward the syntheses of the biologically active alkaloids (-)-galanthamine and (-)-lemonomycin(2006) Fauber, Benjamin Perry; Magnus, Philip D.Despite the enormous amount of work devoted to the synthesis of the anticholinesterase Amaryllidaceae alkaloid, (-)-galanthamine, and the diversity of the various strategies employed, the para-alkylation of an appropriately substituted phenol to generate the cross-conjugated 2,4-cyclohexadienone has not been reported. As discussed in this dissertation, the successful implementation of the intramolecular phenolate alkylation strategy avoids the low yielding phenolic oxidation reaction used previously to generate similar intermediates. The resultant product requires a reductive amination of the aromatic aldehyde and latent aliphatic aldehyde to arrive at racemic narwedine, a biogenetically related and validated synthetic precursor to (-)-galanthamine. A methodology for the construction of enantio-enriched hydroisoquinolines was also developed, with potential application toward the synthesis of the tetrahydroisoquinoline antitumor antibiotic (-)-lemonomycin. Several approaches are discussed, with the key step being an asymmetric reduction of 1-substituted and 1,3-disubstituted isoquinolines to yield enantio-enriched hydroisoquinoline products.Item Studies directed towards the synthesis of (±)-nakadomarin A(2008-08) Garizi, Negar Vosoogh, 1978-; Magnus, Philip D.Herein is described our synthetic efforts toward the synthesis of (±)-nakadomarin A, a member of the manzamine alkaloids. The first chapter describes the isolation and biological significance of (–)-nakadomarin A. Chapter 2 describes the previous total syntheses as well as other partial syntheses of both (–)-nakadomarin A and its unnatural enantiomer. Chapter 3 discusses our approach to the formation of rings A and B in nakadomarin, as well as the installation of the quaternary center and the regioselective incorporation of a hydrazine moiety. Chapter 4 contains the development of a new methodology for the cleavage of hydrazine N-N bonds situated alpha to a carbonyl functionality. Chapter 5 describes the formation of rings D and E. Chapter 6 consists of experimental details and characterization data for all new compounds.Item Studies on the Daphniphyllum alkaloids : strategies towards the synthesis of daphnicyclidin alkaloids(2008-05) Harrington, Ryan Matthew, 1980-; Magnus, Philip D.Herein describes our approaches to the Daphniphyllum alkaloids. Specifically targeted are the recently isolated daphnicyclidins. The first chapter describes the structural diversity and biological properties of this class of alkaloids. Chapter 2 discusses some exploratory chemistry towards the daphnicyclidin fused tricycle. Chapter 3 describes the use of cyclopropanes in synthesis and their use in our ring expansion strategy. Preliminary results on the key cyclopropane ring expansion and the stereoselective quaternary center formation are also discussed. The chemistry concerning the diasteroselective cyclopropanation of a key intermediate and further details concerning the cyclopropane ring expansion are delineated. Chapter 4 contains the experimental details and characterization data for all new reported compounds.Item Studies toward the total synthesis of (±)-chartelline C and (-)-platensimycin(2008-08) Hecker, Evan Adam, 1980-; Magnus, Philip D.Herein is described our work towards the total synthesis of the marine natural product (±)-chartelline C and the potent antibiotic (-)-platensimycin. Part 1 relates the (±)-chartelline C project. The first chapter reviews (±)-chartelline C’s isolation, biogeneity, and previously reported studies relevant to the area. Chapter 2 tells of our contributions including the development of a convergent, regioselective assembly of an indole-imidazole compound en route to the natural product. Chapter 3 includes the experimental details of this work and the characterization of previously unreported compounds. Part 2 recounts the (-)-platensimycin research project. Chapter 4 discusses the importance of the natural product and the relevant previous research reported. Chapter 5 describes our efforts in this area, culminating in the stereoselective synthesis of an intermediate closely related to a known compound, which was converted to the natural product. Chapter 6 includes the experimental details of this work and the characterization of previously unreported compounds.