afforded the sulfoxide 7 in a 91% yield.11 Finally, thermal
elimination of the sulfoxide at 170 °C gave the common
intermediate 10 in a 46% yield.11 The second route utilized
the well-known Garner’s aldehyde, 8. The aldehyde func-
tionality was converted to the olefin 9 via the Wittig reaction
utilizing methyltriphenylphosphonium bromide.12 The iso-
propylidine was then selectively removed with Dowex-M43
to produce the common intermediate 10 in an 80% yield.13
Compound 10 was then converted to the azide 11 in a one-
pot, two-step procedure by first mesylating the primary
alcohol with mesyl chloride and Hunig’s base at -10 °C.
Displacement with sodium azide in DMF at 60 °C produced
11 in a 72% yield over two steps. Removal of the Boc
protecting group to afford 12 was accomplished in a 77%
yield with 4 N HCl in dioxane. The azidoisocyanate 13 was
then obtained in good yield by treatment of 12 with
diphosgene and Proton Sponge.14
temperature, the condensation product 15 was obtained in a
very clean reaction in an 81% yield within 72 h. Unfortu-
nately the product did not spontaneously cyclize to carbamate
3 as it did in the original route. It was necessary to treat 15
with t-BuOK in THF to give 3. This not only provided the
carbamate but also provided the C-10 methyl group as the
natural and desired isomer. To complete the synthesis, the
azide 3 was reduced to the amine and cyclized with PPh3 in
a refluxing THF/H2O mixture, producing the protected
tricycle 4 in a 52% yield.17
It is reasonable to think that the vinyl group might occupy
the same general spatial vicinity as the quinolyl group in
ABT-773 being positioned above the C-13 carbon (Figure
2).18 Compound 4 would thus provide an interesting scaffold,
which could be further elaborated to help probe secondary
ribosomal interactions.
With the azidoisocyanate 13 in hand, we were then able
to construct the erythromycin tricycle 4 (Scheme 3). When
Scheme 3. Improved Synthesis of the Tricyclic Erythromycin
Analogues
Figure 2. Minimized solution conformation of ABT-773.
In conclusion, we have developed a short, efficient, and
high-yielding synthesis of a vinyl tricyclic erythromycin
building block that utilizes a novel azidoisocyanate. This
methodology eliminates the purification and epimerization
problems associated with the original synthesis with greatly
reduced reaction times. Compound 4 provides a structural
motif that will allow for further exploration of secondary
interactions of macrolides within the bacterial ribosome. To
address increasing antibacterial resistance, this research
presents a significant opportunity in the development of new
macrolide antibiotics.
the readily available allylic alcohol 1415 was reacted with
13 and DMAP in toluene at 90 °C, the reaction progressed
to 90% completion within 2 weeks. Although the reaction
was slow, the product was cleanly obtained. It was found,
however, that the reaction could be significantly accelerated
in the absence of heat by treatment with 1 equiv of CuCl.16
Thus, when the azidoisocyanate 13 was condensed with the
allylic alcohol 14 in the presence of CuCl in CH2Cl2 at room
Acknowledgment. The authors would like to thank
Carmina Presto of Department R418 for NMR support and
Rick Clark for his many helpful discussions.
Supporting Information Available: Detailed experi-
mental procedures. This material is available free of charge
(9) Mallams, A. K.; Davies, D. H. U.S. Patent 4180565, 1979.
(10) (a) Kokotos, G. S. Synthesis 1990, 299-301. (b) Kokotos, G.;
Markidis, T. J. Org. Chem. 2001, 66, 1919-1923.
(11) Ohfune, Y.; Kurokawa, N. Tetrahedron Lett. 1984, 25, 1071-1074.
(12) Avenoza. A.; Cativiela, C.; Peregrina, J. M.; Sucunza, D.; Zurbano,
M. M. Tetrahedron: Assymetry 1999, 10, 4653-4661.
(13) Beaulieu, P. L.; Duceppe, J.-S.; Johnson, C. J. Org. Chem. 1991,
56, 4196-4204.
OL047406R
(16) Duggan, M. E.; Imagire, J. S. Synthesis 1989, 131-132.
(17) Unexpectedly, the cyclization of the (R)-isomer did not occur
spontaneously upon reduction of the azide. It was, however, cyclized by
treatment with acetic acid in EtOH at 80 °C to give the cyclized product in
a 20% yield.
(18) See ref 4 and: Or, Y. S.; Clark, R. F.; Wang, S.; Chu, D. T. W.;
Nilius, A. M.; Flamm, R. K.; Mitten, M.; Ewing, P.; Alder, J.; Ma, Z. J.
Med. Chem. 2000, 43, 1045-1049.
(14) Sigurdsson, S. Th.; Seeger, B.; Kutzke, K.; Eckstein, F. J. Org.
Chem. 1996, 61, 3883-3884.
(15) Arouridas, C.; Denis, A.; Auger, J.-M.; Benedetti, Y.; Bonnefoy,
A.; Bretin, F.; Chantot, J.-F.; Dussarat, A.; Fromentin, C.; D’Ambrieres, S.
G.; Lachaud, S.; Laurin, P.; Le Martret, O.; Loyau, V.; Tessot, N. J. Med.
Chem. 1998, 41, 4080-4100.
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