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Cakmak, Mesut (2012): Total synthesis of loline alkaloids and studies toward naphthomycin K. Dissertation, LMU München: Faculty of Chemistry and Pharmacy
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Abstract

Loline is the eponymous member of an alkaloid family, originally isolated in 1892 from tall fescue grasses, but later found in many other plant families. They are produced by endophytic fungi and are as toxic to insects as nicotine, thereby protecting the host plant from herbivores, but many aspects of their chemical ecology are not yet understood. Despite its long history and intriguing biological activity, there has been only one successful asymmetric synthesis of loline to date, which required 20 steps. This may be due to its strained, heterotricyclic molecular skeleton, that incorporates polar functionalities in close proximity, thus rendering the loline alkaloids more challenging targets than they may appear at first sight. This dissertation deals with different approaches for the synthesis of loline alkaloids and reports interesting outcomes. The synthesis, which finally led to success is efficient and asymmetric and requires only 10 steps. The synthesis is scalable, diversifiable, gives access to all loline alkaloids and has served to provide several research groups sufficient material to investigate the interesting chemical ecology of these alkaloids. The naphthomycins are a class of ansamycin antibiotics that contain a macrocycle of polyketide origin with an amide linkage to a naphthalenic moiety. To date, 11 different naphthomycins (naphthomycin A–K) have been isolated and structurally elucidated. In spite of their unique structure and broad spectrum of biological activities, none of the naphthomycins have been synthesized to date. This dissertation includes the syntheses of two building blocks from inexpensive commercially available starting materials in 9 steps each and their coupling in a Horner-Wadsworth-Emmons reaction (HWE) and further transformation to give the C6-C23 fragment of all naphthomycins. In addition, a naphthoquinone precursor has been synthesized starting from a literature known quinone and a novel Danishefsky-type diene. The synthesis of the novel Danishefsky-type diene and its reactivity in Diels-Alder reactions is reported.