Studies Toward the Total Synthesis of ( - )-Apoptolidin PDF Download
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Author: Christina Goudreau Collison
Publisher:
ISBN:
Category :
Languages : en
Pages : 358
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Author: Christina Goudreau Collison
Publisher:
ISBN:
Category :
Languages : en
Pages : 358
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Author: Bin Wu
Publisher:
ISBN:
Category :
Languages : en
Pages : 550
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Author: Gabriel N. Kapur
Publisher:
ISBN: 9781109844450
Category :
Languages : en
Pages : 259
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The northern hemisphere, which had been previously synthesized in our labs, was closely analyzed and synthesized again, with an improvement in the final three steps so that a more isomerically pure product resulted (15:1 now vs. 3:1 before). Finally, a crucial Suzuki coupling reaction of the northern and southern hemispheres was performed, which allowed the diol moiety at C19 and C20 to remain unprotected. This was followed by a saponification reaction to bring us to a very advanced carboxylic acid intermediate, one step from the closed 20-membered macrocycle.
Author: Venkatesan Srinivasan
Publisher:
ISBN:
Category :
Languages : en
Pages : 872
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Author: Douglas J. Tusch
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ISBN:
Category :
Languages : en
Pages : 240
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Author: Xiaorong Liu
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ISBN:
Category :
Languages : en
Pages : 524
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Author: Kyle William Rugg
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ISBN:
Category :
Languages : en
Pages : 307
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"Part I. The Second-Generation Total Synthesis of (-)-Nakadomarin A The second-generation total synthesis of (-)-nakadomarin A (1) has been described. A robust sequence toward the bicyclic lactam has been developed, allowing its production on > 5 g scale. This has been enabled by a number of significant improvements, including increased diastereoselectivity for the key SN2' cyclobutane formation, a scalable cyclobutanecarboximine formation/retro-aza-Claisen sequence, and the removal of a step from the longest-linear sequence by use of isocyanate addition to the bicyclic lactam in lieu of a two-step protocol. The Michael addition/spirocyclization's catalytic potential has been investigated, and a robust and scalable method for the synthesis of the spirocycle has been deployed. After pentacycle formation, macrocyclization, and reduction, (-)-nakadomarin A (1) is afforded with production of the target on over 0.5 g scale. This has resulted in a total synthesis of 1 in 16 steps (longest linear) and 6.5% overall yield. Part II. Studies Toward the Total Synthesis of (-)-Apoptolidin A A route toward the potent and selective apoptosis inducer (-)-apoptolidin A has been outlined. Production of the lactone comprising the southwestern quadrant of the natural product on scale by a previously described route has been investigated. Small-scale success in generating the lactone was ineffective on larger scales using the existing protocol due to the sensitive nature of an intermediate Diels-Alder adduct. Important advancement in material throughput was achieved by implementation of a robust two-step protocol for generating a critical intermediate alcohol on larger scales. Combined with the improvement of a deallylation protocol, a scalable route to the lactone of the southwestern quadrant of (-)-apoptolidin A has been established. With this, the completion of the southern hemisphere and aglycone of (-)-apoptolidin A will be accessible"--Pages x-xi.
Author: Bohan Jin
Publisher:
ISBN:
Category :
Languages : en
Pages : 604
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Author: Lifeng Xiao
Publisher:
ISBN:
Category :
Languages : en
Pages : 433
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"Chapter 1: Studies toward the Total Synthesis of (-)-Apoptolidin A An approach to the total synthesis of the cell apoptosis inducer (-)-Apoptolidin A is described. Our synthetic strategy features the late installation of two sugar units on the core 20-membered macrocycle lactone which can be divided into two advanced subunits allowing for rapid convergence in the forward synthesis. Improvements to couple two subunits to afford the 20-membered macrocycle lactone, the synthesis of the third generation of the northern hemisphere vinyl bromide were developed. This approach involves a smooth transformation from crotyl alcohol to protected dialkyne in eight steps then finished the northern hemisphere through Suzuki coupling. Improvements to the synthesis of subunits vinyl iodide of the southern hemisphere through the synthesis of the bisalkyne subunit via bi-directional chain elongation of a C2 symmetric diepoxide as a key step were optimized. Chapter 2: Bone Targeted Bisphosphonate Conjugates with Releasable Payloads as Prodrugs for the Treatment of Bone Metabolic Diseases. Developments in studies of the invention of novel prodrugs for the treatment of bone metabolic diseases are described. Prodrugs are constituted with a bone selective bisphosphonate, variable linker moiety with bio-reversible carbamate linkage, and biological active parent drugs. These studies have been successful in developing: (1). Bisphosphonate-chloroquine conjugate for the treatment of osteoporosis and rheumatoid arthritis; (2). Bisphosphonate-bortezomib conjugate for the treatment of osteoporosis and multiple myeloma; (3). Bisphosphonate-GSI XII conjugate for the treatment of multiple myeloma; (4). Bisphosphonate-epigenetic inhibitor conjugates for the treatment of bone cancers; and (5). Bisphosphonate-fluorescent labeling conjugate for biologically mechanistic insight studies."--Pages xi-xii.
Author: Qingsong Liu
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Apoptolidin 1.1 was isolated in 1997 by Hayakawa and co-workers from a soil bacterium Nocardiopsis sp. during screening for specific apoptosis inducers. The primary biological test revealed that this polyketide macrolide induced apoptosis in cells transformed with the adenovirus type E1A oncognene, but not normal cells. This dissertation describes the latest studies in understanding of apoptolidin's biological activity mechanism and previous contributions towards its total synthesis. Synthesizing apoptolidinone 1.26 by an intra-molecular Horner-Wadsworth-Emmons approach featuring a Suzuki coupling, cross metathesis and two diastereoselective aldol reactions is discussed. 15 mg apoptolidinone is prepared via our previously developed intramolecular Suzuking coupling approach. Ammocidin 3.1, which was found to induce apoptosis in Ba/F3-v12 cells in an IL- 3 free medium, is a specific apoptosis inducer discovered by Hayakawa and co-workers in 2001 from Saccharothrix sp. AJ9571. A strategy featuring Suzuki coupling, cross metathesis, Yamaguchi macrolactonization and three asymmetric aldol reactions was applied to the total synthesis of ammocidinone 3.6, the aglycone of ammocidin. The preparation of the key building blocks was discussed in the following chapter: aldehyde 3.8 (C14-C19) was synthesized via Sharpless asymmetric epoxidation; ethyl ketone 3.9' (C20-C28) was prepared via Kobayashi and Crimmins's asymmetric aldol methodologies; aldehyde 3.14 (C7-C13) was generated by Brown crotylation and cross metathesis.
