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Chemical Studies Toward the Total Synthesis of Streptogramin Type A Antibodies

出版	University of California, San Diego, and San Diego State University, 2005
URL	http://books.google.com.hk/books?id=KThBAQAAIAAJ&hl=&source=gbs_api

註釋A novel approach toward the synthesis of two key subunits of the streptogramin Type A antibiotic Virginiamycin M1 (VM1) is described. The convergent strategy employed can lead to the production of small libraries of VM1 derivatives, where structure activity relationship (SAR) studies can be conducted in the hopes of creating new and more effective antibiotics. The O 2-C 7 fragment of VM1 is produced in high yield with excellent stereoselectivity by taking advantage of Evans boron aldol chemistry to introduce stereocenters, and utilizing novel aqueous Wittig chemistry developed in the Bergdahl group. The C 9- C 23 fragment poses several synthetic challenges which are addressed herein. A palladium-mediated cross-coupling reaction is employed to create the allylic diene amine present in the fragment, an acetate aldol reaction generates the chiral alcohol, and a functionalized oxazole is synthesized to be introduced into the fragment via a samarium-mediated coupling reaction. Iodotrimethylsilane (TMSI) promoted conjugate addition reactions utilizing novel monoorganocopper reagents, Li[RCuI], result in high yields and diastereroselectivities of products when various chiral oxazolidinones and pyrrolidinones are employed as substrates. This atom economical alternative to the traditional Gilman reactions proved most successful for asymmetric conjugate addition reactions to chiral imides when compared to a wide variety of well studied reagent systems. Novel aqueous Wittig reactions are carried out producing olefin products in high yields and isomeric ratios. Often, the rate of the Wittig reaction is significantly accelerated in water compared to conventional Wittig reactions in organic solvents. This novel methodology can be applied to the synthesis of natural products, as demonstrated by its effectiveness in the construction of the O 2-C 7 fragment of VM1.