Browsing by Author "Daniel L. Comins, Committee Chair"

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Alkaloid Synthesis Using N-Acylpyridinium Salts as Building Blocks: Progress Towards the Total Synthesis of (-)-FR901483 and Synthesis of Novel Polyheterocyclic Compounds
(2003-06-26) Gotchev, Dimitar Borissov; Daniel L. Comins, Committee Chair; Suzanne T. Purrington, Committee Member; Bruce Novak,, Committee Member; Binghe Wang, Committee Member
A study directed toward the total synthesis of the potent immunosuppressant (-)-FR901483 was examined. Three approaches to the tricyclic core of the targeted molecule were investigated, utilizing Grignard addition to an N-acylpyridinium salt and quaternary center formation as the key synthetic steps. In the first route, a pivotal keto-aldehyde intermediate was needed to study an intramolecular pinacol coupling approach to the backbone of the title compound. In the second and third generation synthetic designs, an intramolecular 6-exo-tet epoxide opening was envisioned as a means of generating the azabicyclo ring system of the target. Three novel polyheterocyclic ketones were synthesized in a flexible manner in search for an asymmetric epoxidation catalyst of unfunctionalized trans-alkenes. The targeted compounds were derived via a regiospecific alkylation of 5-hydroxy-2-methylpyridine, followed by functional group manipulation and nitrogen atom cyclization.
Catalyst Design for Asymmetric Organozinc Addition to Aldehydes and Progress Toward the Total Synthesis of the Marine Alkaloid, (-)-Lepadiformine.
(2006-05-10) Marks, Lucas Richard; Daniel L. Comins, Committee Chair; Christian Melander, Committee Member; Suzanne T. Purrington, Committee Member; T. Brent Gunnoe, Committee Member
A novel dihydropyridone was synthesized in search for a chiral ligand for the asymmetric addition of an alkyl group to an aldehyde. The target amine was derived from an enamine through a hydrogenation reaction. A study directed toward the total synthesis of the marine alkaloid (-)-lepadiformine was carried out. Two approaches were investigated toward the core perhydroquinoline system. The first approach utilized a Grignard addition to an N-acylpyridinium salt and a [2+2] photochemical addition as the key synthetic steps. The second approach was based upon quinoline chemistry. The model study was completed with a one-carbon alkene homologation to form a terminal butane. An asymmetric route was examined.
PartI. Study of 1-Acyl-2-dimethylphenylsilyl-2,3-dihydro-4-pyridone as Synthetic Intermediates. Part II. Synthesis of Nicotine Derivatives from Nicotine.
(2005-07-19) Smith, Emilie Despagnet; Daniel L. Comins, Committee Chair
Various methodologies were investigated to build synthetic intermediates from 1-acyl-2-dimethylphenylsilyl-2,3-dihydro-4-pyridones and to synthesize nicotine derivatives from nicotine. In the first part of this document, the synthesis and reactivity of 1-acyl-2-dimethylphenylsilyl-2,3-dihydro-4-pyridone were investigated. This dihydropyridone was synthesized from the addition of dimethylphenylsilyl Grignard to the 1-acyl-4-methoxypyridinium salt with a 90% yield and 98% de. A variety of reactions including 1,4-additions and the synthesis of the corresponding dihydropyridine was accomplished. In the second part, various methodologies were discovered to synthesize enantiopure nicotine derivatives from nicotine. Regioselective substitution reactions for functionalization at C-4, C-5 and C-6 of the pyridine ring were achieved. The synthesis of novel C-4 substituted and unsubstituted dihydronicotines was also developed. The von Braun reaction was applied to give enantiopure pyrrolidine ring-opened products.
Progress Toward the Synthesis of Apomorphine: Chiral Auxiliary Mediated Interception of an Intramolecularly Formed N-Acyl Iminium Ion
(2004-03-16) Nuckols, Michel Christian; Daniel L. Comins, Committee Chair; Suzanne Purrington, Committee Member; Carl Bumgardner, Committee Member; James K. Whitesell, Committee Member
Glaucine, which contains an aporphine skeleton, has been previously synthesized utilizing an intermolecular approach to form an iminium ion for the Pictet-Spengler reaction. A diastereomeric excess of 79% resulted as mediated by a chiral auxiliary. Progress was made in attempting to increase the diastereomeric excess by using an intramolecular approach to iminium ion formation. Apomorphine is a suitable platform on which to demonstrate the asymmetric interception of a chiral N-acyl iminium ion generated by intramolecular means. Several routes to this end were explored. These routes included the use of an intramolecular variant on the previously published work, Grubbs' metathesis and Horner-Wadsworth-Emmons among others. While no route proved successful in the end, understanding of the formation of aporphine skeletons was expanded upon.
Studies Toward the Total Synthesis of the Lycopodium Alkaloid Spirolucidine Using the N-Acyl-2,3-dihydro-4-pyridone as a Building Block
(2005-04-04) Young, Damian Winston; Daniel L. Comins, Committee Chair; Suzanne T Purrington, Committee Member; Jonathan S. Lindsey, Committee Member; Bruce M. Novak, Committee Member
Spirolucidine is a complex alkaloid isolated from the club moss Lycopodium lucidulum. A three fragment convergent plan for the title compound was envisioned, with each fragment being derived from a chiral N-acyl-2,3-dihydro-4-pyridone. The synthesis of the bicyclic enecarbamate referred to as zone C was investigated. The first effort centered on a tandem intramolecular Diels-Alder reaction/retro Mannich ring opening reaction to set the key stereogenic centers within zone C. A second strategy aimed to ring open the tricyclic adduct which arises from the Diels-Alder reaction through an E1cB mechanism. Finally, a third attempt was made to utilize chirality transfer as a means to implement the necessary stereochemical elements of the bicyclic scaffold. The convergent union of the key fragments of spirolucidine was modeled on a simple substrate. The directed lithiation of N-Boc-dihydropyridines was utilized to prepare model 2,5,6-trisubstituted dihydropyridones of a general type needed for the completion of the spirolucidine synthesis.
The Synthesis of (S)-Camptothecin and Clinically Useful Analogs
(2003-12-01) Nolan, Jason Michael; Daniel L. Comins, Committee Chair
A six-step synthesis of (S)-camptothecin (CPT) was completed relinquishing a fast, efficient route to this natural product. The key steps included the formation of the 4-iodo-2,3-pyridylacetal intermediate 56 required to obtain the DE ring moiety of CPT, and an intramolecular Heck reaction for the closure of ring C. The convergence of this synthesis provided a straightforward method for CPT-analog development. Application is displayed in the syntheses of the clinically useful CPT-derivatives Karenitecin BNP1350 and the Irinotecan precursor 66. These syntheses are highlighted by short, high-yielding routes to the tetra- and tri-substituted quinoline rings, respectively. The DE ring portion of homocamptothecin (hCPT) was completed utilizing the same key intermediate 56 of the CPT synthesis. Although racemic, this seminal synthesis is very concise, being significantly shorter than known protocols. An investigation for the use of 2-haloquinolines as synthetic building blocks in CPT-analog development was completed. Attempts to use directed ortho-metallation (DoM) chemistry on 2-chloro-3-quinolinecarboxaldehyde and derivatives proved to be inapplicable. However, regioselective lithium-halogen exchange and palladium-catalyzed coupling reactions were discovered for 2,4-dihaloquinolines. This success provides a versatile method for synthesizing highly substituted quinolines.
Synthesis of Nicotine Derivatives from Natural Nicotine, Total Synthesis of (S)-Brevicolline, and Advances towards the Synthesis of Dihydrolycolucine.
(2006-08-10) Wagner, Florence Fevrier; Coby Schal, Committee Member; Christian C. Melander, Committee Member; Daniel L. Comins, Committee Chair; T. Brent Gunnoe, Committee Member; Suzanne Purrington, Committee Member
Nicotine and its derivatives are currently being synthesized and tested to explore their pharmaceutical capabilities in the treatment of Alzheimer's disease, Parkinson's disease, and other central nervous system disorders. One area of research the Comins group has been undertaking is the development of methodologies for the synthesis of nicotine derivatives from natural nicotine. Herein, regioselective substitutions of the pyridine ring of (S)-nicotine will be described. Efforts are underway to expand the scope of these methods and to apply them to the preparation of potential pharmaceuticals, insecticides, synthetic intermediates, and novel ligands for catalytic asymmetric synthesis. Nicotine was used as a building block for the syntheses of SIB-1508Y, a potential anti-Parkinson's drug, which was successfully synthesized enantiomerically pure in only five steps. (S)-Brevicolline, a natural product of the -carboline family was synthesized from nicotine in only six steps. Our goal is to transform inexpensive, commercially available (S)-nicotine from an underutilized natural product to a useful member of the chiral pool. Our group previously reported the intramolecular Diels-Alder reaction of 1-acyl-2-alkenyl-1,2-dihydropyridines. A derivative of a dihydropyridine Diels-Alder product could be ring-opened via a Retro-Mannich reaction to give a cis-decahydroquinoline derivative. The potential of this methodology for the synthesis of dihydrolycolucine, natural product from the Lycopodium family, prompted us to carry the model studies described in Chapter IV.