Ryan E. Looper, University of Utah
Synthetic platform: Given the
range of structural diversity in these natural products in respect to ring
size, oxidation state and substitution we aimed to develop a unified synthetic
platform to access these skeletons. In pursuance of our 1) provide access to
predictable and controlled substitution patterns in short order, 2) deliver these diverse hydrogen bond topologies, and 3)
permit
ring oxidation state adjustments within these cyclic or polyclic
structures. We
felt that the addition of a guanidine N-H bond across a C-C p-system would represent a powerful
tool for the preparation of these challenging heterocyles.
The development of amine-alkene/alkyne hydroamination
chemistry has provided an invaluable tool for the construction of nitrogen
based heterocycles. The extension of this methodology
to guanidines, however, remains largely
underdeveloped. In order to manipulate the oxidation states of these
heterocyclic cores we anticipated that this is best done by reduction, as
oxidations of nitrogen rich heterocycles are usually
problematic. This has led us to study the addition of guanidine N-H bonds across
alkynes, thus providing access to cyclic structures at an elevated oxidation
state (Figure 2). This disconnection also permits the rapid construction of
diverse skeletal precursors via an imine-acetylide
3-component coupling. To this end we examined the utility of an addition-hydroamination-isomerization sequence (Figure 3). (Angew. Chem. Int. Ed. 2009, 48, 3116-3120). This strategy provided access to a variety of
highly substituted 2-aminoimidazoles in just 3 steps and was generally high
yielding. Further, the introduction of a removable R group permitted the
preparation of any desired hydrogen bond donor-acceptor topology. We have also been able to adapt this
reaction sequence to the addition of thiols, phenols
and alcohols (Figure 5, J. Org. Chem.
2010, 75, 261-264). Consistent with what we had
learned from the addition of amines to the cyanamides,
this chemistry requires a fine balance of nucleophilicity
and basicity to effect addition to the cyanamide
without formation of the allenyl-cyanamide which
readily decomposes. This manifold presents an interesting polarity reversal for
the preparation of these heterocycles which are
usually constructed by the addition of an intact thiourea
or urea to an electrophile. The major limitation of this methodology was that the
addition of a nucleophile to the cyanamide was rate
limiting and
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