Organic Letters
Letter
natural product meridianin C in 88% yield without the need for
chromatography.
Pd(PPh3)4, K3PO4, MeCN) generated the desired azaindole
system, which was immediately deprotected by the one-pot
acid/base procedure described above to generate the 5-bromo
analog 24 in 55% yield over two steps.
In conclusion, a new approach to the meridianins and
meriolins utilizing the Cacchi indole synthesis has been
developed and can be used to provide rapid access to natural
and synthetic members of the meridianin family of natural
products. It is anticipated that this method will be of use in the
synthesis of further analogs of meridianins and meriolins and
allow further studies of the biological properties of these
families of compounds.
In addition to preparing natural members of the meridianin
family, the Cacchi-type domino process can also be used to
prepare novel analogs of the natural meridianins. Sonagashira
coupling of readily available iodide 1320 with TMS-acetylene,
followed by mesylation, gave sulfonamide 14. Coupling of
sulfonamide 14 with pyrimidine 8 under the conditions
developed gave protected meridianin 15 in 76% yield. Global
deprotection of 15 gave the non-natural 6-methoxymeridianin
G 16 in 76% yield.
While our method was successful at producing members of
the meridianin class of natural products, extension of this
protocol to the synthesis of the meriolins initially hit a
stumbling block, as it was not possible to prepare the
monomesylated aminopyridine starting material 17 by the
reaction of aminopyridine 1821 with mesyl chloride and
pyridine. Despite numerous attempts, the only product isolated
was the dimesylated material and efforts to remove one of the
mesyl groups and/or utilize the dimesyl compound in the
domino amino-palladation protocol failed to yield any of the
desired products. This issue was eventually resolved by first
acylating aminopyridine 18 with trifluoroacetyl anhydride to
yield the monotrifluoroacetamide, followed by a reaction with
mesyl chloride and NEt3 (Scheme 5). Upon workup of this
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and characterization for compounds
are available with copies of 1H and 13C NMR spectra for all new
compounds. This material is available free of charge via the
AUTHOR INFORMATION
■
Corresponding Author
Notes
Scheme 5
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by an ARC Discovery Grant
(DP0706503).
REFERENCES
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reaction, the TFA group was cleaved affording the mono-
mesylated pyridine 19 in 71% yield over two steps. The
reaction of 19 with iodide 8 using our optimized conditions (5
mol % Pd(PPh3)4, K3PO4, MeCN) gave the desired azaindole
23, which was immediately globally deprotected using the one-
pot acid/base process to generate meriolin 1 in 51% yield for
the two steps. To further illustrate the utility of the protocol, 5-
bromomeriolin 1 was synthesized from bromide 20.22 The
sulfonamide 22 was prepared in 56% overall yield by first
introducing the silylalkyne by a Sonogashira coupling (TMS
acetylene, CuI, PdCl2(PPh3)2, NEt3) on bromide 21, followed
by the two step sequence (TFAA, THF; then MsCl, NEt3,
THF) to selectively introduce a single methanesulfonamide
group onto the amino group. The reaction of sulfonamide 22
with iodide 8 using the optimized conditions (5 mol %
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C
dx.doi.org/10.1021/ol403390m | Org. Lett. XXXX, XXX, XXX−XXX