Total synthesis of loline alkaloids and studies toward naphthomycin K

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.