Page 286 - Advanced Organic Chemistry Part B - Reactions & Synthesis

258 Scheme 3.6. (Continued)

CHAPTER 3
a. R. E. Kent and S. M. McElvain, Org. Synth., III, 490 (1955).
Functional Group b. A. C. Cope and E. Ciganek, Org. Synth., IV, 339 (1963).
Interconversion c. R. M. Herbst and D. Shemin, Org. Synth., II, 11 (1943).
by Substitution, d. B. B. Corson, R. W. Scott, and C. E. Vose, Org. Synth., I, 179 (1941).
Including Protection and e. C. F. H. Allen and J. Van Allen, Org. Synth., III, 765 (1955).
Deprotection f. D. J. Abraham, M. Mokotoff, L. Sheh, and J. E. Simmons, J. Med. Chem., 26, 549 (1983).
g. J. Diago-Mesenguer, A. L. Palamo-Coll, J. R. Fernandez-Lizarbe, and A. Zugaza-Bilbao, Synthesis, 547 (1980).
h. R. J. Bergeron, S. J. Kline, N. J. Stolowich, K. A. McGovern, and P. S. Burton, J. Org. Chem., 46, 4524 (1981).
i. W. Wenner, Org. Synth., IV, 760 (1963).
j. C. R. Noller, Org. Synth., II, 586 (1943).

3.5. Installation and Removal of Protective Groups

Protective groups play a key role in multistep synthesis. When the synthetic target
is a relatively complex molecule, a sequence of reactions that would be expected to lead
to the desired product must be devised. At the present time, syntheses requiring 15–20
steps are common and many that are even longer have been completed. In the planning
and execution of such multistep syntheses, an important consideration is the compat-
ibility of the functional groups that are already present with the reaction conditions
required for subsequent steps. It is frequently necessary to modify a functional group in
order to prevent interference with some reaction in the synthetic sequence. A protective
group can be put in place and then subsequently removed in order to prevent an
undesired reaction or other adverse influence. For example, alcohols are often protected
as trisubstituted silyl ethers and carbonyl groups as acetals. The silyl group masks both
the acidity and nucleophilicity of the hydroxy group. An acetal group can prevent both
unwanted nucleophilic additions or enolate formation at a carbonyl group.

R OH + R′ SiX R O SiR′ 3
3
R C O + R′OH R 2 C(OR′) 2
2

Three considerations are important in choosing an appropriate protective group:
(1) the nature of the group requiring protection; (2) the reaction conditions under which
the protective group must be stable; and (3) the conditions that can be tolerated for
removal of the protecting group. No universal protective groups exist. The state of the
art has been developed to a high level, however, and the many mutually complementary
protective groups provide a great degree of flexibility in the design of syntheses of
complex molecules. 149 Protective groups play a passive role in synthesis, but each
operation of introduction and removal of a protective group adds steps to the synthetic
sequence. It is thus desirable to minimize the number of such operations. Fortunately,
the methods for protective group installation and removal have been highly developed
and the yields are usually excellent.

3.5.1. Hydroxy-Protecting Groups

3.5.1.1. Acetals as Protective Groups. A common requirement in synthesis is that
a hydroxy group be masked as a derivative lacking the proton. Examples of this
requirement are reactions involving Grignard or other strongly basic organometallic

149
T. W. Green and P. G. Wuts, Protective Groups in Organic Synthesis, 3rd Edition, Wiley, New York,
1999; P. J. Kocienski, Protective Groups, Thieme, New York, 2000.