Protecting Groups
Use of protecting groups documents our inability to do synthesis properly (in contrast to biosynthesis). The disadvantages that go along with the use of protecting groups can be minimized by a proper choice of short-term, medium-term, and long-term protec
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Protecting Groups
Abstract Use of protecting groups documents our inability to do synthesis properly (in contrast to biosynthesis). The disadvantages that go along with the use of protecting groups can be minimized by a proper choice of short-term, medium-term, and long-term protecting groups, when in situ protection schemes and the use of latent functionality is not available.
During the synthesis of a complex target, synthetic organic chemists have grown accustomed to using protecting groups in order to shield particular functional groups from the threat of reagents and reaction conditions necessary for elaboration elsewhere in the molecule. In recent decades a whole arsenal of protecting groups for all conceivable functional groups has been developed [1, 2]. Scheme 7.1 illustrates the protecting group pattern of the
H 8HN
H
O
H
H
O7 O H
O3
O7 H O
3O
1 = Me
O3
3O
2 = COCH3
O3
3 = Si(Me)2tBu
3O
O3
4 = CH 2C6H4OMe
Me 3O
O3
5 = COC6H5
O2
O3
O3
6 = Me
O3 O4 4O O
O3
Me
Me 4O
1O O2 Me
Me O
H
O4
O2
H
O H
O4
3O
O4 O
O4 O6 H O
MeO
5O
O3 O3
O4
4O
H
7 = acetonide
O H
O2
O3
H
O3
O3 O2
5O
H O
3O
Me
8 = (CO)OCH2CH2SiMe3
O2
Ref. [3]
O5
Scheme 7.1 Protecting group pattern in the final phase of the synthesis of palytoxin carboxylic acid
R.W. Hoffmann, Elements of Synthesis Planning, c Springer-Verlag Berlin Heidelberg 2009 DOI 10.1007/978-3-540-79220-8 7,
119
120
7 Protecting Groups
epochal synthesis of palytoxin carboxylic acid [3], an enterprise that involved eight different types of protecting groups (42 in all). Each of these had to be introduced individually, and the whole flock had to be removed at the very end of the synthesis in five separate steps. The universal (and frequently promiscuous) use of protecting groups is a telltale sign that chemists are not (yet) in a position to do synthesis right! Protecting groups normally require two operations (introduction and removal)— which, strictly speaking, are counterproductive, since they reduce the overall efficiency of the synthesis. While nature generates the most complex natural products without recourse to protecting groups, a protecting group free synthesis [4, 5, 6, 7] of even small multifunctional molecules, such as Fleet’s synthesis of muscarine [8], cf. also [9] (Scheme 7.2), appears exceptional for most chemists. OH
OH
HO
OH
HO
Br2
OH
HO
+
OH
O
O
Et3N
MeOH HO
O
Py
HO
79 %
H O
O 58 %
HO LiBH4
Pd
H O
HO
75 %
H2 H O
O
H O
OSO2Me
OSO2Me
+
H
OSO2Me
MeSO2Cl
HO
TFAA
HO
OH
H2O
BaCO3 O
H
NaOAc OH
O 76 %
H
O
H
68 %
HO TolSO2Cl Py
Me3N H3C
+ NMe3 H O H
52 %
Ref. [8]
Scheme 7.2 Protecting group free synthesis of muscarine
Given the present state of synthetic methodology, the choice of protecting groups is a central issue in synthesis planning. It cannot be overstated that a single protecting group being too reactive or too unreactive may cause the failure of the whole synthetic endeavor, as happened with efforts from our own group [10, 11]. If extra steps
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