served to produce the thiomethyl imidate 17.11,12 To effect
the key electrocyclization step,13,14 heating N-vinyl imidate
17 in a dilute solution of mesitylene at 145 °C for 16 h
afforded the desired imidazolopyridine 19 (44% isolated
yield, 51% based on recovered starting material 17). The
major byproduct detected in this process appears to be the
isomerized (E)-vinyl imidate 20 (27%).
Scheme 5
To continue the synthesis, sulfide 19 was first treated with
m-CPBA to produce mainly sulfoxide 21a (76%) along with
a smaller amount of the corresponding sulfone 21b (10%)
(Scheme 5). This mixture was subsequently treated with
sodium azide in DMSO at room temperature to afford the
2-azidoimidazole 22 in good yield. The azide was then
reduced by hydrogenation over Lindlar catalyst to afford
amine 23 in 94% yield. After some experimentation, it was
found that both BOM protecting groups can be removed by
exposure of intermediate 23 to anhydrous aluminum tri-
chloride15 in methylene chloride at room temperature,
affording ageladine A (1) identical with material that we have
previously synthesized.3
ageladine A (1) that features as the key step a thermal 6π-
2-azatriene electrocyclization for construction of the imid-
azolopyridine system. This new convergent synthesis requires
only seven steps from easily prepared (Z)-vinyl iodide
imidazole fragment 10 and dibromopyrrole amide 14, and
the approach would appear to be amenable to facile synthesis
of structural analogues of the natural product.
In conclusion, we have completed a biogenetically inspired
total synthesis of the antiangiogenic marine metabolite
(11) In some extensive studies with model enamide A we were unable
to directly form any imidate derivatives B
Acknowledgment. We are grateful to the National
Science Foundation (CHE-0404792) for financial support of
this research and Dr. H. Yennawar (Penn State Small
Molecule X-ray Crystallographic Facility) for the X-ray
structure determination of dibromopyrrole 14. We also thank
Professor Blake Peterson and Jocelyn Edathil (Penn State
University) for assistance with reverse phase HPLC analysis.
.
(12) The NMR spectra of thioimidate 17 show broad peaks (see the
Supporting Information) which might be due to rapid inversion of the imine
nitrogen.
(13) Cf.: (a) Biere, H.; Russe, R.; Seelen, W. Liebigs Ann. Chem. 1986,
1749. (b) Qiang, L. G.; Baine, N. H. Tetrahedron Lett. 1988, 29, 3517. (c)
Palacios, F.; Gil, M. J.; Martinez de Marigorta, E.; Rodriguez, M.
Tetrahedron 2000, 56, 6319. (d) Campos, P. J.; Caro, M.; Rodriguez, M.
A. Tetrahedron Lett. 2001, 42, 3575.
(14) For a general review of triene electrocyclizations see: Okamura,
W. H.; de Lera, A. R. 1,3-Cyclohexadiene Formation Reactions. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, UK, 1991; Vol. 5, pp. 699-750.
(15) Groves, J. K.; Cundasawmy, N. E.; Anderson, H. J. Can. J. Chem.
1973, 51, 1089.
Supporting Information Available: Experimental pro-
cedures for preparation of new compounds including X-ray
and spectral data. This material is available free of charge
OL063038A
Org. Lett., Vol. 9, No. 5, 2007
855