Progress Towards the Total Synthesis of (-)-Batrachotoxin A Computationally Inspired Second-Generation Synthesis of (+) Fastigiatine Progress Towards the Total Synthesis of (-)-Himeradine A and Strategies Towards the 4,5-Spirocyclic Fragment of Phainanoid F PDF Download
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Author: Jacob Cole DeForest Publisher: ISBN: 9780355307559 Category : Languages : en Pages : 411
Book Description
The first chapter of this dissertation focus on the history and syntheses of the bioactive steroidal alkaloid (--)-batrachotoxin. Several notable partial syntheses are discussed, as well as two total synthesis. Previous efforts by the Rychnovsky group, as well as our current route towards batrachotoxin are described in Chapter 2. The successful synthesis of fully elaborated AB and DE steroidal fragments are disclosed, as well as the key reductive fragment coupling and Heck cyclization to form the steroidal core.Chapters 3 provides a concise introduction to the Lycopodium family of natural products, while Chapters 4 and 5 describe our recent efforts towards the total synthesis of two Lycopodium alkaloids, (+)-fastigiatine and (--)-himeradine A. Following the successful first-generation synthesis of fastigiatine, we chose to pursue a modified second-generation route that was inspired by computationally modeling. Highlights of the synthesis include a diastereoselective reduction-ketalization, an optimized dibromocarbene mediated ring-expansion, and utilization of photoredox catalysis to perform a radical aminomethylene conjugate addition. In Chapter 5, our efforts towards the total synthesis of himeradine A are disclosed. A highly efficient racemic synthesis of an advanced tri-substituted piperidine was achieved, and several methods to perform a late-stage resolution are discussed. A proof-of-concept Suzuki coupling between the quinolizidine precursor and pentacyclic core precursor was successful. Elaboration of the coupled intermediate through the remainder of the synthesis was accomplished, confirming the validity of our approach towards the synthesis of himeradine A.Finally, several strategies towards the synthesis of the 4,5-spirocyclic fragment of phainanoid F are presented in Chapter 6. While initial efforts on a model system were unsuccessful due to unexpected carbocation rearrangements, a route involving the photochemical Wolff ring contraction proved to be an efficient method to access the cyclobutane moiety found in the natural product. This approach is currently being applied towards the enantioselective synthesis of the western fragment of phainanoid F.
Author: Jacob Cole DeForest Publisher: ISBN: 9780355307559 Category : Languages : en Pages : 411
Book Description
The first chapter of this dissertation focus on the history and syntheses of the bioactive steroidal alkaloid (--)-batrachotoxin. Several notable partial syntheses are discussed, as well as two total synthesis. Previous efforts by the Rychnovsky group, as well as our current route towards batrachotoxin are described in Chapter 2. The successful synthesis of fully elaborated AB and DE steroidal fragments are disclosed, as well as the key reductive fragment coupling and Heck cyclization to form the steroidal core.Chapters 3 provides a concise introduction to the Lycopodium family of natural products, while Chapters 4 and 5 describe our recent efforts towards the total synthesis of two Lycopodium alkaloids, (+)-fastigiatine and (--)-himeradine A. Following the successful first-generation synthesis of fastigiatine, we chose to pursue a modified second-generation route that was inspired by computationally modeling. Highlights of the synthesis include a diastereoselective reduction-ketalization, an optimized dibromocarbene mediated ring-expansion, and utilization of photoredox catalysis to perform a radical aminomethylene conjugate addition. In Chapter 5, our efforts towards the total synthesis of himeradine A are disclosed. A highly efficient racemic synthesis of an advanced tri-substituted piperidine was achieved, and several methods to perform a late-stage resolution are discussed. A proof-of-concept Suzuki coupling between the quinolizidine precursor and pentacyclic core precursor was successful. Elaboration of the coupled intermediate through the remainder of the synthesis was accomplished, confirming the validity of our approach towards the synthesis of himeradine A.Finally, several strategies towards the synthesis of the 4,5-spirocyclic fragment of phainanoid F are presented in Chapter 6. While initial efforts on a model system were unsuccessful due to unexpected carbocation rearrangements, a route involving the photochemical Wolff ring contraction proved to be an efficient method to access the cyclobutane moiety found in the natural product. This approach is currently being applied towards the enantioselective synthesis of the western fragment of phainanoid F.
Author: Justin Adam Hilf Publisher: ISBN: 9781339563848 Category : Languages : en Pages : 123
Book Description
Part I of this dissertation presents the efforts directed towards the total synthesis of batrachotoxin. The general approach focuses on the construction of the C ring of the steroid backbone through two carbon-carbon bond forming reactions. This approach breaks the complex natural product into two more approachable pieces. The AB ring system was accessed from the Hajos-Parish ketone and was coupled to the elaborated D ring by a conjugate addition/Claisen rearrangement sequence to form one of the desired carbon-carbon bonds. Extensive effort has been made in an attempt to cyclize the C ring.Part II describes the development of a new approach to the synthesis of substituted pyridines. The method aims to provide a reliable synthesis of a diverse scope of substituted pyridines through a concise three step procedure. Readily available enones are first converted into 1,5-dicarbonyls through a two-step Sakurai allylation/oxidative cleavage sequence, which is followed by subsequent cyclization to the corresponding pyridine using hydroxylamine hydrochloride. A variety of substituted pyridines have been synthesized using this method.
Author: Amber Reilly Publisher: ISBN: 9781124420738 Category : Languages : en Pages : 179
Book Description
Part I of this dissertation presents the studies directed toward the total synthesis of batrachotoxin. The general approach towards the synthesis of batrachotoxin involves preparation of the AB rings and the DE rings independently, followed by union of these two ring systems, subsequent closure of the C ring, and elaboration to the natural product. A deconjugative alkylation approach has thus far proved to be the most reliable route to the union of the AB rings to the DE rings, however other methods should be explored. Model studies and synthesis of advanced intermediates have provided a good foundation for future work towards the synthesis of batrachotoxin. Part II of this dissertation presents the studies directed toward the total synthesis of Phorboxazole B with an emphasis on efforts for uniting the side chain and macrocyclic core of the natural product by Wittig olefination. Model studies provided detailed insight into the conditions that would be optimal for union of these two advanced intermediates. While these model studies indicated a promising outcome and were even performed on highly elaborate model compounds, these conditions did not translate well in the union of the real side chain and macrocyle of Phorboxazole.
Author: Brian Liau Publisher: ISBN: Category : Languages : en Pages : 0
Book Description
Part one of this two-part thesis describes my efforts toward the total syntheses of the complex polycyclic alkaloids himeradine A and fastigiatine, which are members of the Lycopodium family of natural products. A cascade reaction sequence featuring a biosynthesis-inspired transannular Mannich reaction was planned to construct the strained and densely functionalized pentacyclic cores of the molecules from acyclic starting materials. After difficulties were encountered in a first-generation synthesis plan toward himeradine A, a second-generation synthesis plan was eventually successful in accomplishing the first total synthesis of fastigiatine via a formal [3+3]-cycloaddition reaction and a retro-aldol tandem transannular Mannich reaction sequence. In part two of this thesis, syntheses of the hibarimicin aglycons, including HMP-Y1, atrop-HMP-Y1, hibarimicinone, atrop-hibarimicinone, and HMP-P1, are reported. These natural products are amongst the largest and most complex type-II polyketides isolated. A novel benzylic fluoride Michael-Claisen reaction sequence was developed to construct the complete carbon skeleton of HMP-Y1 and atrop-HMP-Y1 via a symmetrical bidirectional double annulation reaction. Through efforts to convert HMP-Y1 derivatives to hibarimicinone and HMP-P1, a biomimetic mono-oxidation to desymmetrize protected HMP-Y1 was realized. A bidirectional unsymmetrical double annulation and biomimetic etherification were developed to construct the polycyclic and highly-oxidized skeleton of hibarimicinone, atrop-hibarimicinone, and HMP-P1. Lastly, a pH-dependent rotational barrier about the C2-C2 & rsquo bond of hibarimicinone was discovered, which provides valuable information for achieving the syntheses of the glycosylated congeners of hibarimicinone.
Author: Jacob Cole DeForest
Author: Jacob Cole DeForest
Author: Justin Adam Hilf
Author: Amber Reilly
Author: Brian Liau