A growing number of fluorine-containing
active ingredients in the
pharmaceutical and agrochemical industries inevitably raises the demand
for new fluorinated building blocks. Their availability is mainly
constricted by suitable chemistry and available bulk fluorine containing
starting materials. Because of the high cost impact especially in
the agrochemical industry, the choice of a synthetic route is heavily
driven by economic aspects; thus, the environmental profile often
is handled as a “secondary factor” or finally falls
aside. DFMMP is a key building block for a fast growing new fungicide
family, like Syngenta’s Sedaxane, and BASF’s Fluxapyroxad
and Bayer’s Bixafen currently made by environmetally less friendly
routes. Herein we present a cost-competitive and green route, developed
at Solvay laboratories, displaying significantly lower environmental
impact.
Two macrocyclic aminoglycosides were prepared from a 1,4-butanediol linked 2-deoxy-L-rhamnal which was O-allylated at the 4- and 4'-positions via the precursor allyl 3,4-di-O-acetyl-2,6-dideoxy-alpha-L-arabino-hexoside employing olefin metathesis and ring closing metathesis in a sequential manner. The macrocycles were 15N-labelled at all four amino groups in order to study interactions with regulatory RNA structures in solution by NMR spectroscopy. A key step for the introduction of the 15N-label was a reductive amination step using commercially available 15NH4OAc. The reductive amination proceeds with excellent stereocontrol. As a by-product the unusual acyclic amino nitrile was isolated which originated from intramolecular imine formation followed by cyanide addition to the intermediate C=N double bond.
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