Page 256 - Advanced Organic Chemistry Part B - Reactions & Synthesis

228 combination. 49 Carboxylate alkylation procedures are particularly advantageous for
preparation of hindered esters, which can be relatively difficult to prepare by the acid-
CHAPTER 3
catalyzed esterification method (Fisher esterification), which we discuss in Section 3.4.
Functional Group During the course of synthesis, it is sometimes necessary to invert the configu-
Interconversion
by Substitution, ration at an oxygen-substituted center. One of the best ways of doing this is to activate
Including Protection and the hydroxy group to substitution by a carboxylate anion. The activation is frequently
Deprotection
50
done using the Mitsunobu reaction. Hydrolysis of the resulting ester give the alcohol
of inverted configuration.
OH Ph 3 P
CH 3 DEAD PhCO 2
CH 3 O O CH 3
H H CO CH PhCO H CH 3 H
2
H
3
2
CO 2 CH 3 89%
Ref. 51
P
Ph 3 O
O DEAD
HO O PhCO 2 O
PhCO H 74%
3
Ref. 52
Carboxylate anions derived from somewhat stronger acids, such as p-nitrobenzoic
acid and chloroacetic acid, seem to be particularly useful in this Mitsunobu inversion
53
reaction. Inversion can also be carried out on sulfonate esters using cesium carboxy-
lates and DMAP as a catalyst in toluene. 54 The effect of the DMAP seems to involve
complexation and solubilization of the cesium salts.
Sulfonate esters also can be prepared under Mitsunobu conditions. Use of zinc
tosylate in place of the carboxylic acid gives a tosylate of inverted configuration.

CH 3
CH 3
Ph P
3
DEAD
HO
Zn(O SAr) ArSO 3
CH 2 CCH 3 3 2
CH 2 CCH 3 96% Ref. 55
The Mitsunobu conditions also can be used to effect a variety of other important
and useful nucleophilic substitution reactions, such as conversion of alcohols to mixed
56
phosphite esters. The active phosphitylating agent is believed to be a mixed phospho-
ramidite.

49
T. Sato, J. Otera, and H. Nozaki, J. Org. Chem., 57, 2166 (1992).
50
D. L. Hughes, Org. React., 42, 335 (1992); D. L. Hughes, Org. Prep. Proc. Intl., 28, 127 (1996).
51 M. J. Arco, M. H. Trammel, and J. D. White, J. Org. Chem., 41, 2075 (1976).
52 C.-T. Hsu, N.-Y. Wang, L. H. Latimer, and C. J. Sih, J. Am. Chem. Soc., 105, 593 (1983).
53
J. A. Dodge, J. I. Tujillo, and M. Presnell, J. Org. Chem., 59, 234 (1994); M. Saiah, M.Bessodes, and
K. Antonakis, Tetrahedron Lett., 33, 4317 (1992); S. F. Martin and J. A. Dodge, Tetrahedron Lett., 32,
3017 (1991); P. J. Harvey, M. von Itzstein, and I. D. Jenkins, Tetrahedron, 53, 3933 (1997).
54 N. A. Hawryluk and B. B. Snider, J. Org. Chem., 65, 8379 (2000).
55 I. Galynker and W. C. Still, Tetrahedron Lett., 4461 (1982).
56
I. D. Grice, P. J. Harvey, I. D. Jenkins, M. J. Gallagher, and M. G. Ranasinghe, Tetrahedron Lett., 37,
1087 (1996).