LETTER
Efficient Stereoconservative Angeloylation of Alcohols
2651
(8) (a) Bal-Tembe, S.; Bhedi, D. N.; De Souza, N. J.; Rupp, R.
H. Heterocycles 1987, 26, 1239. (b) Hoskins, W. M.; Crout,
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lization steps provided 1 from ingenol in a total yield of
31%.
In summary, through investigating and optimizing the key
angeloylation reaction, we can synthesize ingenol 3-an-
gelate on large scale with only minimal isomerization in
the last step. We have explored the scope of our stereo-
conservative angeloylation protocol, which proved to be
general and applicable for various types of alcohols. We
believe the method of using pure angelic anhydride and a
suitable base will find wide use in the future in the prepa-
ration of angelate esters, which often are moieties of nat-
ural products. However, it should be pointed out that the
present method may not be suitable for substrates which
do not tolerate strong bases. In those cases, our method
cannot replace Beeby’s and Greene’s methods. We have
also discussed a likely mechanism for the cause of the
isomerization when using DMAP or pyridine (cf. the
mechanistic study of the analogous isomerization during
reductive amination of 3,3-disubstituted propenals7).
Even though this isomerization phenomenon has been ob-
served previously,8c,11 DMAP and pyridine still find use in
such reactions.8d–h,9,12k,l Thus, we would like to point out
that care must be taken when nucleophilic bases like pyr-
idine and DMAP are used on substrates capable of acting
as reversible Michael acceptors and also with the interpre-
tation of published experiments under similar conditions.
(c) Nakayama, J.; Nakamura, Y.; Tajiri, T.; Hoshino, M.
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Acknowledgment
Krygowski, E. S.; Wood, J. L. J. Org. Chem. 2001, 66, 7025.
(l) Adams, R. P.; Dev, V. Flavour Fragr. J. 2010, 25, 71.
(11) Hartmann, B.; Kanazawa, A. M.; Depres, J.-P.; Greene, A.
E. Tetrahedron Lett. 1991, 32, 5077.
We acknowledge Thomas Vifian, Christina Dahl Schmidt, and Ka-
rin Kryger for skillful technical assistance. We thank Kevin Dack
for proofreading.
(12) (a) Liu, W.; Dong, W.; Liao, X.; Yan, Z.; Guan, B.; Wang,
N.; Liu, Z. Bioorg. Med. Chem. Lett. 2011, 21, 1419. (b) Wu,
Y.-C.; Zhu, J. Org. Lett. 2009, 11, 5558. (c) Wright, B. J. D.;
Chan, C.; Danishefsky, S. J. J. Nat. Prod. 2008, 71, 409.
(d) Merten, J.; Hennig, A.; Schwab, P.; Fröhlich, R.;
Tokalov, S. V.; Gutzeit, H. O.; Metz, P. Eur. J. Org. Chem.
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Supporting Information for this article is available online at
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Synlett 2012, 23, 2647–2652