the oxygen substituents in the same position as the parnafun-
gins rearranges fastest with a half-life of 6 days. Tetracycle
10 rearranges with a half-life of 10 days and tetracycle 22b
rearranges slowest with a half-life of 27 days. The C-methyl
group of m-methoxytoluene is deprotonated twice as fast as
that of toluene by lithium amide bases, whereas the C-methyl
group of o-methoxytoluene is deprotonated 10 times slower
than that of toluene.12 Deprotonation occurs in the rate-
determining step of an E2 elimination even if protonation
of the carbonyl group by adventitious HCl is the initial step.
Therefore, the two methoxy groups meta to the methylene
group of 26c should accelerate deprotonation and E2
elimination, whereas the methoxy groups ortho and para to
the methylene group of 22b should retard deprotonation and
elimination. The parnafungins have oxygen substituents meta
to the methylene group as in 26c and a carbonyl group para
to the methylene group, which should further increase its
acidity and accelerate the E2 elimination.
presumably by air. The autoxidation of hydroxylamine in
aqueous base has been extensively studied13 and the oxida-
tion of alkylhydroxylamines to oximes in MeOH has been
reported.14 The formation of 29 by this decomposition
pathway is noteworthy because we were unable to prepare
29 directly by oxidation of 27a using procedures that work
well on phenanthridine iteself. Both electron-withdrawing
groups and peri substituents are known to retard the
N-oxidation of heterocycles.15
In conclusion, a practical route to the labile tetracyclic
isoxazolo[4,3,2-de]phenanthridinone moiety (10 and 26c) of
the antifungal parnafungins has been developed. Zinc reduc-
tion of methyl 2′-hydroxymethyl-2-nitro-3-biphenylcarboxy-
lates 24a and 24c, which were prepared by Suzuki couplings,
afforded benzisoxazolones 25a and 25c that were treated with
MsCl and then base to generate the labile tetracyclic ring
systems 10 (37%) and 26c (47%). These compounds rear-
range to phenanthridines 27a and 27c in CDCl3 and 10
decomposes to phenanthridine N-oxide 29 in aqueous base.
We also explored the decomposition of 10 under basic
condition with NaOD in CD3CN/D2O. Under these condi-
tions, we detected an intermediate with the CH2 group shifted
upfield to δ 4.32 from δ 4.72 in 10. We tentatively assigned
structure 28 to this intermediate (see Scheme 8). To our
Acknowledgment. We are grateful to the National Insti-
tutes of Health (GM-50151) for support of this work. We
thank Professor Stephen Buchwald, Massachusetts Institute
of Technology for advice on Suzuki couplings.
Supporting Information Available: Complete experi-
mental procedures, copies of 1H and 13C NMR spectral data.
This material is available free of charge via the Internet at
Scheme 8. Decomposition of 10 in Base
OL901054R
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