Angewandte
Communications
Chemie
devised on the basis of intermediates 17, 20, and 21, the
accepted mechanism postulated for the aminoarylation
[
11]
overall number of synthetic steps was likely to far exceed
reaction.
We initially speculated that the originally
[
4a,b]
[4f,h]
those required by the Overman,
Martin,
and Kwon
formed aminoarylation product might have undergone epi-
merization, or that the arylation reaction might take place
without the assistance of the amino group. However, deuter-
ation and control experiments failed to support these spec-
ulations (Scheme 5a,b). Interestingly, cleavage of the Teoc
[4i]
groups. Therefore, an alternative desymmetrization solu-
tion had to be identified to ensure comparable overall
efficiency.
Gratifyingly, our continued efforts in desymmetrization
ultimately led to the discovery of a cycloaddition process that
proved highly effective on diene 5 (Scheme 2). In this
instance, the bromonitrile oxide generated in situ from
dibromooxime 6 underwent regioselective [2+3] cycloaddi-
tion with diene 5 to afford isoxazoline 7 in 68% yield as
[
10]
a single stereoisomer. The use of KHCO was previously
3
[
10b]
adopted by the Baran group,
was routinely performed on a gram scale with excellent
reproducibility. Bromoisoxazoline further underwent
and the optimized procedure
7
methoxy substitution (MeOLi) and oxidation (DDQ) to
afford isoxazole 8, a masked b-ketoester with a concealed
carboxylate group and the desired C2 (actinophyllic acid
numbering) oxidation state for actinophyllic acid (1).
At this juncture, following the selective functionalization
of two of the three olefins in triene 2, the remaining alkene in
8
was poised to undergo an arylation reaction to render
a substrate for late-stage indolization. Moreover, the pro-
posed arylation could be made more appealing by synchro-
nizing it with the formation of the adjacent pyrrolidine, a dual
objective well-suited for the palladium-catalyzed aminoary-
[
11]
lation reaction developed by Wolfe and co-workers. Teoc
carbamate 8 was first treated with TFA to unmask its
secondary amine while leaving the acid-labile dioxolane
intact, and the resulting amine·TFA salt was directly sub-
jected to the aminoarylation conditions. The yield of amino-
arylation product 10 varied depending on the reaction
conditions (Scheme 4; see also the Supporting Information).
The choice of aryl halide, phosphine ligand, base, and solvent
were all examined. Although an increase in the catalyst
loading had a positive effect on the reaction yield, we opted
for a lower catalyst loading for economic reasons and
routinely recycled the crude reaction mixture.
Scheme 5. Probing the stereochemical course of the aminoarylation
reaction (see the Supporting Information for details).
carbamate, followed by workup with aqueous NaHCO3,
afforded cyclized pyrrolidine 22 (Scheme 5c), a compound
that failed to undergo arylation under our standard reaction
conditions (Scheme 5d). At the present, our working model
for the observed stereochemical outcome is consistent with an
anti-aminoarylation pathway instead of the originally antici-
pated syn-aminoarylation (Scheme 5e), in which the electro-
philic palladium center together with the conformational
constraint that prohibited proper PdÀN and C=C alignment
The stereochemical assignment of aminoarylation product
1
0 was established on the basis of extensive 2D NMR studies,
and although inconsequential for our synthesis, the observed
stereostructure was not in agreement with the generally
would appear to favor anti-aminoarylation under reversible
[12]
palladation conditions. Furthermore, coordination of the
palladium center with a dioxolane oxygen atom could also
[
13]
contribute to the observed stereochemical outcome.
With nitroarene 10 in readiness for the planned indoliza-
tion, the requirement to reduce its nitro group together with
the rupture of the isoxazole moiety motivated us to execute
both reductive events as a single operation, followed by
spontaneous indolization (Scheme 2). This proposed cascade
transformation proved nontrivial in practice. In particular, the
isoxazole moiety was resilient towards a variety of reducing
conditions examined. Ultimately, upon removal of the
Scheme 4. Summary of the optimization of the aminoarylation. All
reactions were performed under an Ar atmosphere (see the Supporting
Information for details).
dioxolane moiety in 10 (HCl, MeOH), PdCl -catalyzed
2
hydrogenation successfully afforded the targeted indole 12.
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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