The human 20S proteasome inhibitor
scytonemide A (<b>1</b>), a macrocyclic imine originally isolated
from the cyanobacterium <i>Scytonema hofmanni</i>, was synthesized
via a biomimetic solid-phase
peptide synthesis (SPPS) approach employing the Weinreb AM resin.
Utilizing this approach, cyclization of the protected heptapeptide
via formation of the imine bond occurred spontaneously upon cleavage
from the resin in the presence of a reducing agent and subsequent
aqueous workup. The final deprotection step necessary to produce the
natural product was accomplished under slightly basic conditions,
facilitating cleavage of the silyl ether group while leaving the macrocycle
intact. Purification of the synthetic scytonemide A was accomplished
via normal-phase flash column chromatography, potentially facilitating
larger scale preparation of the compound necessary for future mechanistic
and SAR studies. The structure of the target compound was confirmed
by NMR spectroscopy, which also shed light on differences in the spectroscopic
data obtained for the synthetic and natural scytonemide A samples
for some of the amide and alcohol signals in the <sup>1</sup>H NMR
spectrum
