Catalysis-Based Total Syntheses of Pateamine A and DMDA-Pat A

The marine natural product pateamine
A (1) and its
somewhat simplified designer analogue DMDA-Pat A (2)
(DMDA = desmethyl-desamino) are potently cytotoxic compounds; most
notably, 2 had previously been found to exhibit a promising
differential in vivo activity in xenograft melanoma
models, even though the ubiquitous eukaryotic initiation factor 4A
(eIF4A) constitutes its primary biological target. In addition, 1 had also been identified as a possible lead in the quest
for medication against cachexia, an often lethal muscle wasting syndrome
affecting many immunocompromised or cancer patients. The short supply
of these macrodiolides, however, rendered a more detailed biological
assessment difficult. Therefore, a new synthetic approach to 1 and 2 has been devised, which centers on an
unorthodox strategy for the formation of the highly isomerization-prone
but essential Z,E-configured dienoate
substructure embedded into the macrocyclic core. This motif was encoded
in the form of a 2-pyrone ring and unveiled only immediately before
macrocyclization by an unconventional iron-catalyzed ring opening/cross-coupling
reaction, in which the enol ester entity of the pyrone gains the role
of a leaving group. Since the required precursor was readily available
by gold catalysis, this strategy rendered the overall sequence short,
robust, and scalable. A surprisingly easy protecting group management
together with a much improved end game for the formation of the trienyl
side chain via a modern Stille coupling protocol also helped to make
the chosen route practical. Change of a single building block allowed
the synthesis to be redirected from the natural lead compound 1 toward its almost equipotent analogue 2. Isolation
and reactivity profiling of pyrone tricarbonyliron complexes provide
mechanistic information as well as insights into the likely origins
of the observed chemoselectivity.