Abstract:
Two efficient, regio- and stereo controlled synthetic approaches to the
synthesis of racemic analogs of pancratistatin have been accomplished and they serve
as the model systems for the total synthesis of optically active 7-deoxy-pancratistatin.
In the Diels-Alder approach, an efficient [4+2] cycloaddition of 3,4-methylenedioxyco-
nitrostyrene with Danishefsky's diene to selectively form an exo-nitro adduct has
been developed as the key step in the construction of the C-ring of the target
molecule. In the Michael addition approach, the key step was a conjugate addition of
an organic zinc-cuprate to the 3,4-methylenedioxy-(B-nitrostyrene, followed by a
diastereocontroUed closure to form the cyclohexane C-ring of the target molecule via
an intramolecular nitro-aldol cyclization on a neutral alumina surface. A chair-like
transition state for such a cyclization has been established and such a chelation
controlled transition state can be useful in the prediction of diastereoselectivity in
other related 6-exo-trig nitroaldol reactions. Cyclization of the above products fi^om
both approaches by using a Bischler-Napieralski type reaction afforded two
lycoricidine derivatives 38 and 50 in good yields.
The initial results from the above modeling studies as well as the analysis of
the synthetic strategy were directed to a chiral pool approach to the total synthesis of
optically active 7-deoxy-pancratistatin. Selective monsilylation and iodination of Ltartaric
acid provided a chiral precursor for the proposed key Michael transformation.
The outlook for the total synthesis of 7-deoxy-pancratistatin by this approach is very
promising.A concise synthesis of novel designed, optically pure, Cz-symmetrical
disulfonylamide chiral ligands starting from L-tartaric acid has also been achieved.
This sequence employs the metallation of indole followed by Sfj2 replacement of a
dimesylate as the key step. The activity for this Cz-symmetric chiral disulfonamide
ligand in the catalytic enantioselective reaction has been confirmed by nucleophilic
addition to benzaldehyde in the disulfonamide-Ti (0-i-Pr)4-diethylzinc system with a
48% yield and a 33% e.e. value. Such a ligand tethered with a suitable metal complex
should be also applicable towards the total synthesis of 7-deoxy-pancratistatin.
