Browsing by Author "Ciufolini, Marco A."
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Item A new benzannulation reaction(1994) Weiss, Trent Jason; Ciufolini, Marco A.A new benzannulation reaction was discovered. The reaction involves intramolecular attack into a carbon-carbon triple-bond by the alpha position of a beta-ketoester under acidic conditions. Four different beta-ketoester starting materials were prepared and were successfully cyclized. This benzannulation methodology should provide a convenient pathway for forming aromatic products to be used as building blocks in the syntheses of anti-tumor antibiotics.Item A new methodology for the total synthesis of mitomycinoid FR900482(1998) Chen, Mingying; Ciufolini, Marco A.We describe the application of a novel ene-like reaction developed in our laboratory to the facile preparation of benzazocinone and benzazocenone intermediates of the type 3. Thus, ene-like reaction of 1 with 2-methoxypropene furnished adduct 2. This material underwent tandem intramolecular 1,3-dipolar azide cycloaddition and photolysis of the resulting triazoline to give 3. (DIAGRAM, TABLE OR GRAPHIC OMITTED...PLEASE SEE MAI) The newly developed avenue to these medium-ring heterocycles should be useful in a total synthesis of the antitumor agent, FR900482, 4. A synthesis of the highly substituted aldehyde 6, which could produce intermediates 5 suitable for the ultimate elaboration into 4 by the new chemistry, has also been developed.(DIAGRAM, TABLE OR GRAPHIC OMITTED...PLEASE SEE MAI)Item A novel ene reaction: Development and applications to the synthesis of (+,-)-phyllanthocin(1996) Deaton, Melissa Virginia; Ciufolini, Marco A.A new reaction has been discovered that forms carbon-carbon bonds at room temperature under catalysis by lanthanide reagents. This reaction occurs between vinyl ethers, which have an oxygen functionality located at the central carbon of the allylic system, and aldehydes and is catalyzed by a 1:1 complex of Yb(fod)$\sb3$ and AcOH. The primary product, 3, is not observed but becomes protected, in situ, by excess vinyl ether present as the solvent, or co-solvent, to form the observed product 4. This reaction is very general and proceeds to form pure vinyl ether products in excellent yields. The vinyl ether products formed through the use of this novel reaction can be used to quickly piece together more complex functionalities such as furanones, cyclopentanes, bromoketones, and benzazepinones. Approaches to the efficient syntheses of these compounds and others will be discussed. Phyllanthocin, 5, the aglycon of the potent antitumor agent Phyllanthoside, has been targeted for synthesis using the ene reaction. Furanone formation, using a functionalized vinyl ether formed in the ene reaction, is the primary goal. Applications to the total synthesis of Phyllanthocin will be discussed.$\sp*$ ftn$\sp*$Please refer to the dissertation for diagrams.Item A unified approach to mitomycinoids: Application of a novel ene-like reaction(1999) Lovett, Dennis Paul; Ciufolini, Marco A.A practical synthesis of the powerful antitumor agents, mitomycin C and FR900482, remains an elusive goal to this date. These substances may be thought to arise from suitably functionalized benzazocinones as retrosynthetic intermediates. The key to a unified strategy for the synthesis of all mitomycinods is thus a concise, efficient route to a common benzazocenone, which requires appropriate substituents on the aromatic ring as dictated by the specific target molecule. The preparation of medium ring heterocycles of this type is troublesome. The research described herein has been directed toward the development of a practical solution to this problem. We describe the application of our novel ene-like reaction for the construction of benzazocinone intermediates as well as research towards various methods to transform them into suitable intermediates for the total synthesis of mitomycinoids. We also developed an efficient method for construction of properly functionalized aldehydes for our ene-like reaction, as well as the synthesis of an achiral diol which can be desymmetrized for use in an enantiocontrolled synthesis. The information accumulated from these experiments will, undoubtedly, be helpful in completion of the total synthesis of FR900482 and other mitomycinoids, which continues in our laboratories.Item Application of a novel carbonyl ene reaction: Total syntheses of phyllanthocin and chlorovulone II(1998) Zhu, Shuren; Ciufolini, Marco A.We describe the total syntheses of $(\pm)$-phyllanthocin (1), the aglycon of the potent antineoplastic agent phyllanthoside (2a), and of $(\pm)$-chlorovulone II (3), a halogenated marine prostanoid with high antiproliferative and cytotoxic activity.* The key step of both syntheses is a novel carbonyl ene reaction, which occurs between ordinary aldehydes and vinyl ethers that display the oxygen functionality at the central carbon of an allylic system, e.g., 2-methoxypropene, under the catalytic influence of 0.5 mol% of the 1:1 complex of Yb(fod)$\sb3$ and acetic acid (Figure I).* ftn*Please refer to dissertation for diagrams.Item Applications of a novel pyridine-forming reaction: The total syntheses of kuanoniamine D, dercitins, and lavendamycin methyl ester(1993) Bishop, Michael Joseph; Ciufolini, Marco A.Several bioactive thiazolopyridoacridines of marine origin have been synthesized. Kuanoniamine D was synthesized in 18 steps from cyclohexanedione mono-ethyleneketal in 7.3% overall yield. The most potent member of the family, dercitin, was also synthesized from cyclohexanedione mono-ethyleneketal in 18 steps and 7.2% overall yield. Nordercitin was produced from the same starting material in 16 steps and 9.3% overall yield. This work also confirms the revision of the controversial structural assignments of dercitin and nordercitin. These efficient total syntheses include a new pyridine-forming sequence and a photochemical nitrene insertion as crucial steps. A novel approach to the streptonigrinoids, a family of potent antitumor antibiotics, is also described. An efficient formal total synthesis of the methyl ester of lavendamycin has been completed to demonstrate the usefulness of this approach. Key steps include a new pyridine-forming sequence and a thermolytic nitrene insertion to form a $\beta$-carboline. This formal synthesis is several steps shorter and an order of magnitude more productive than previously reported synthetic approaches.Item Conversion of methoxy vinyl ethers into glyoxal ketals(1996) Dilzer, Kirsten France; Ciufolini, Marco A.A technique for the elaboration of ene products derived from aldehydes and 2-methoxypropene into glyoxal monoketals 5 has been devised, and some reactions of the resulting aldehydes have been examined. This methodology should resolve some difficulties encountered in the course of an ongoing total synthesis of phyllanthocin. Key phases of the present study involve oxidation of ether 1, readily available from butyraldehyde through a novel ene-type reaction discovered in our laboratory, using mCPBA and methanol to give a cyclic ketal 2. The resulting seven-membered ring was opened by ketal exchange with 1,3-propanethiol to give thioketal diol 3. Benzylation of the diol proceeded with complete selectivity for the primary alcohol, permitting differentiation of the diol functionality. Protection of the secondary alcohol as a MOM derivative and subsequent ketal exchange with bis(trifluoroacetoxy)iodobenzene reinstated the dimethoxy ketal. Debenzylation under Birch conditions released the free primary alcohol 4, Swern oxidation of which yielded the desired aldehyde 5.* ftn*Please refer to the dissertation for diagrams.Item New approaches to total synthesis of quinoid antitumor agents: Cystodytins and discorhabdins(1991) Byrne, Norman Edward; Ciufolini, Marco A.A new pyridine synthesis is described. The key step involves a modified Knoevenagel-Stobbe reaction in which the treatment of an alkoxy-dihydropyran with hydroxylamine hydrochloride generates highly substituted pyridine ring systems. Approaches to efficient syntheses of important natural products in including aza-analogs of polynuclear aromatic hydrocarbons, Eupolauramine, and Streptonigrin are explored. Antitumor agents Cystodytin A and B were synthesized in 13 steps from 4-hydroxyethyl cyclohexanone in an overall yield of 7%. This efficient total synthesis involves the new pyridine reaction and a photochemical nitrene insertion as crucial steps. Various approaches are explored toward the total synthesis of antitumor agent Discorhabdin C. The first synthetically useful Paterno-Buchi reaction between benzoquinone and an olefin was discovered. Various applications of this reaction are described, including its use for the synthesis of Discorhabdin C.Item New synthetic reactions: Applications to discorhabdins and carbacephems(1996) Dong, Qing; Ciufolini, Marco A.A novel approach for the synthesis of antitumor agents Discorhabdins (1) is described. The synthetic route features a new Paterno-Buchi photo reaction for the spirocyclic ring preparation and cascade Michael reactions for the construction of pyrrolidine unit. The preparation of an advanced intermediate (2) will be discussed.(DIAGRAM, TABLE OR GRAPHIC OMITTED...PLEASE SEE DAI) A parallel investigation deals with the application of an Aza-Achmatowicz rearrangement for the synthesis of carbacephems. Both cis and trans series of bicyclic $\beta$-lactams were easily available through the Aza-Achmatowicz sequence.(DIAGRAM, TABLE OR GRAPHIC OMITTED...PLEASE SEE DAI)Item Photocycloaddition of quinones to olefins: Mechanism and applications(1993) Rivera Fortin, Maria Angelica; Ciufolini, Marco A.Photochemical reactions between benzoquinones and alkylidenecyclohexanes proceed regioselectively. Regioselectivity is determined by the conformational properties of the cyclic olefin. Photocycloadducts thus obtained may be used for the construction of important alkaloidal frameworks in synthetically useful yields. Oxetane formation is likely to occur through concerted collapse of an exciplex that possesses considerable charge transfer character.Item Studies on complex pyridine alkaloids: Total synthesis of cystodytin J, diplamine, shermilamine B and of Micrococcin P1(1998) Shen, Yongchun; Ciufolini, Marco A.Concise, efficient total syntheses of cystodytin J, diplamine and shermilamine B have been accomplished. These cytotoxic marine alkaloids display a novel pyridoacridine architecture that was readily assembled by a combination of two new processes developed in our laboratory: a pyridine-forming reaction and a photochemical insertion of a triplet nitrene into a C-H bond. The overall yield of diplamine is 12% over 7 steps. The synthesis of shermilamine B involves 11 steps with the overall yield of 8%. The first total synthesis of the antitumor agent, Micrococcin P1, a member of the biologically important family of thiostrepton antibiotics, is also described. Central to the success of this endeavor was the development of a greatly improved Hantzsch-type pyridine forming reaction. Additional chemical technologies featured in this synthesis include the use of transformations that remove the need for extensive purification of the various intermediates, the use of specially protected threonine units as precursors to the dehydroaminoacid components of micrococcin, extensive use of chemoselective thionation reactions in the presence of multiple reactive functionality, minimal protection, and closure of a 26 member ring. The longest linear sequence involves 23 steps and the overall yield along this pathway is 5.7%Item Studies towards the synthesis of complex 1,2 amino alcohols(1990) Spencer, George Otis, III; Ciufolini, Marco A.A novel method for the synthesis of complex 1,2 amino alcohols of syn stereochemistry has been achieved via the condensation of $\gamma$-oxygenated allylstannanes with activated imines. The imines are activated by an N-aryl group, and boron trifluoride etherate. The N-aryl functionality serves to delocalize the negative charge developing on nitrogen. Imines with both N-aryl/C-aryl and N-aryl/C-aliphatic functionality have been prepared, and condensed with various allylstannanes. Previously unknown N-aryl/C-aliphatic imines have been synthesized for the first time, using a modified Wadsworth-Emmons reaction. The syn stereochemistry of the reaction has been proven by NOEDS of the oxazolone derivatives of the condensation products. The 4-carbomethoxyphenyl (4-CMP) group has been developed as an excellent activating group for the imine. The facile removal of this functionality has been demonstrated by use of the Birch reduction.Item Synthesis of Phenanthroizidine Alkaloids and a Practical Total Synthesis of (208)-(+)-Camptothecin(1997) Roschangar, Frank; Ciufolini, Marco A.; Engel, Paul S.; Rudolph, Frederick B.Chapter I describes the total syntheses of the representative phenanthroizidine alkaloids tylophorine, antofine and of their seco congeners, septicine and julandine, which have been accomplished through the CiufoliniByrne pyridine synthesis. Chapter II discusses the evolution of our strategy for the synthesis of (208)-( + )-Camptothecin.Item Synthetic applications of the aza-Achmatowicz rearrangement(1990) Hermann, Cynthia Wood; Ciufolini, Marco A.A novel method for the enantioselective synthesis of nitrogen containing compounds has been achieved. The oxidative rearrangement of N-acyl 2-furylamines, termed the Aza-Achmatowicz rearrangement, generates a product with a high density of differentiable functionalities. This characteristic of the product makes it an excellent building block for the synthesis of nitrogenous substances of biomedical interest. Optically pure building blocks are also available via the Aza-Achmatowicz rearrangement. The generation of chirality in the starting furyl derivative is obtained by a simple, inexpensive chemoenzymatic method utilizing papain. The chemical reactivity of these heterocycles has been thoroughly explored, and utilized in the synthesis of (+)-desoxoprosopinine, deoxyazasaccharides, izidinie alkaloid systems, $\beta$-lactams, and unusual amino acids.Item Synthetic studies of luzopeptins(1997) Xi, Ning; Ciufolini, Marco A.Luzopeptins are a series of cyclic depsipeptides which possesses potent antitumor and antiviral activities. There is no total synthesis of Luzopeptins has been achieved. In our own effort to synthesize the luzopeptins, we developed a concise and practical route to PCA, 86, and an efficient protocol to synthesize the mono-BOC, 181. A novel serinyl chloride was devised in conjunction with the formation of PCA-serine dipeptide derivatives, 164. All these methodologies were successfully applied to the synthesis of monomeric derivative of luzopeptin E$\sb2,$ 288.* ftn*Please refer to the dissertation for diagram.Item Synthetic studies on the discorhabdins(2000) Yates, Matthew H.; Ciufolini, Marco A.The discorhabdins are a family of chemically and biologically interesting natural products. Previous syntheses of these complex substances have all been very similar; this similarity is limiting to the flexibility of these approaches. We describe a general method which we believe can diverge to make any number of the natural products. This route is based on novel benzoquinone photochemistry followed by an annulation onto a quinone monoketal to give the core structure. This core can then be advanced appropriately to form the natural products.* *Please refer to dissertation for diagrams.Item Synthetic studies toward an advanced intermediate of Fredericamycin A and the development and application of a novel palladium(0)-mediated spiroarylation(1991) Browne, Margaret Elizabeth; Ciufolini, Marco A.An advanced intermediate 2 for the synthesis of antitumor antibiotic ($\pm$)-Fredericamycin $A$, 1, has been prepared. The synthetic route features a novel palladium(0)-mediated intramolecular spiroarylation of 3. This methodology allows access to the unusual spirocyclic ring skeleton characteristic of Fredericamycin $A$ from more readily accessible precursors, isoquinoline 4 and naphthalide 5. The syntheses of 4 and 5 are discussed. Preliminary model studies established an efficient pathway to structures related to 3. These initial studies also disclosed a means by which to generate spirocyclic ring systems of the type found in Fredericamycin $A$. (DIAGRAM, TABLE OR GRAPHIC OMITTED...PLEASE SEE DAI)Item Synthetic studies towards the luzopeptins: New amino acid synthons through the aza-Achmatowicz reaction(1992) Shimizu, Toshio; Ciufolini, Marco A.A new method for the enantioselective synthesis of unusual amino acids has been developed. The chemoenzymatic aza-Achmatowicz rearrangement of appropriate furylglycine derivatives provided nitrogenous synthons that were readily converted to amino acid building blocks. An application of the new chemistry to the synthesis of the unique pyridazine carboxylic acid component of luzopeptins is presented. Luzopeptin C has potent inhibitory activity towards the reverse transcriptase of HIV as the causative agent of AIDS.