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A Challenging Synthesis of the Highly Functionalized Echinocandin ASP9726: A Successor of Micafungin
Here,
we describe a practical, scalable, and challenging synthesis
of the highly functionalized novel echinocandin ASP9726 (<b>1</b>) starting from the natural product FR901379 (<b>3</b>), which
is a starting material of micafungin (<b>2</b>). The synthesis
includes transformations that address significant synthetic challenges
due to the need to control the chemoselectivity of the reactions during
modification of the highly functionalized peptide core. In the present
study, we discovered an efficient, high-yielding route to ASP9726
(<b>1</b>) that is suitable for large-scale production. Namely,
dehydration of carboxamide (<b>14</b>) to nitrile (<b>15</b>) was accomplished by use of EDC·HCl with pyridine. Further,
the transformation of nitrile (<b>15</b>) to primary amine (<b>17</b>) was conducted via hydrogenation with Sponge Nickel catalyst
without decomposition, followed by one-pot debenzylation with Pd/C.
Reductive amination between primary amine (<b>17</b>) with dihydroxyacetone
(DHA) was accomplished using 2-picoline/borane complex as a reducing
agent in MeOH, yielding 66.6 kg of peptide core unit (<b>18</b>). After the C<sub>15</sub>H<sub>31</sub> chain cleavage by bioconversion,
reductive amination between the core peptide unit (<b>4</b>)
and side chain (<b>10</b>) was achieved in high yield by making
use of <i>tert</i>-butyl amine/borane complex as a reducing
agent. Consequently, highly pure ASP9726 (<b>1</b>) was obtained
in a practical manner without using silica gel or ODS column chromatography
purification in any step. Overall yield was drastically increased
from 0.71% to 13.8% compared to that of the prior synthetic method