METHODS DEVELOPMENT
Inspired by the Ru-catalyzed ring-opening metathesis polymerization (ROMP) of norbornenes shown below,
we have been investigating the scope of tandem ring-opening-ring-closing-cross metathesis sequences for
the synthesis of complex ring systems in the context of natural products synthesis.
We have developed a new process to access mixed polyketide that allows for the coupling of complex subunits at the same time as the formation of tetrahedral stereochemistry. This reaction employs the reductive cyclization of (silyloxy)enynes with a Ti(IV) source and a Grignard reagent and proceeds very reliably to yield only a single diastereoisomer:
This reaction was featured as the key step in our very concise synthesis of
7-demethylpiericidin A1, and also served as an alternative to crotylation in the
context of our dictyostatin synthesis.
We have also recently developed a strategy using Ti(II) chemistry to couple
complex subunits via the intermediacy of the Kulinkovich cyclopropanation.
Reaction of alkenes with an ester in the presence of a Ti(II) species affords
the expected cyclopropanols. Ring-opening of the cyclopropanol in the presence of an
Fe(III) source and 1,4-cyclohexadiene or tin hydride gives a ketone and
establishes a process that is the synthetic equivalent of a direct reductive coupling
of an alkene with an ester. Alternatively, opening of the cyclopropanol with FeCl3
in the presence of NCS and DBU generates a product that would formally result from direct
acylative coupling of an alkene with an ester. In both cases this strategy
avoids the need to resort to multi-step processes for the formation of Grignard
or lithium reagents and the use of Weinreb amides.
We envisage that this approach should be of substantive general utility in the context
of complex molecule synthesis and an example from our recent work on spirastrellolide is shown below:
