The synthesis of the
13-keto-10-azabicyclo[7.3.1]enediyne core structure of
dynemicin A has been achieved
by two routes, Schemes and . The chemistry of the 13-keto core
structure is dominated by the unusually facile
bridgehead enolization. Comparison of the rates of
cycloaromatization of a variety of enediynes revealed that
substantial rate differences occurred even though the distance between
the bonding acetylenes was virtually identical.
A non-radical cycloaromatization pathway, initiated by thiol
addition to the enediyne system, was discovered, and
the simple core amine 26 exhibits modest in vitro
and in vivo antitumor activity. Finally, two methods
for the
synthesis of the naphtho[2,3-h]quinoline portion
of dynemicin A are described, and both these compounds
also
exhibit antitumor activity.
The dynemicin core azabicyclo[7.3.1]enediyne 2 is readily synthesized in five steps from the quinolines 9 or 13; the chemistry of the core enediyne is dominated by its ready enolization.The unusual structure and potent antitumour activity of dynemicin A 1 have made it a topical subject for synthetic and molecular modelling/recognition studies. f-As an extension of our research on esperamicin and calicheamicin, we have applied the key $-C%( CO)6-propargyl cation cyclization strategy for the synthesis of cyclic ten-membered ring enediynes to the synthesis of the azabicyclo[7.3. llenediyne core structure 2, Scheme 1.1The $-Co2( CO),j-propargyl alcohol complex 4 should ionize under electrophilic conditions to give 3, which upon oxidative decomplexation provides an exceptionally short route to the azabicyclo[7.3.l)enediyne 2.
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