Acid Hydrolysis / Base Hydrolysis / Hydrogenolysis

1. removed in basic conditions The Use of Orthogonally Stable Protecting Groups Acid Hydrolysis / Base Hydrolysis / Hydrogenolysis

2. Fluoride-Labile Protecting Groups in Combination with Oxidation-Labile Functions

5. Modulated Lability of Silyl Protecting Groups

6. Relative stability of silyl ethers R-O-SiR’3 The lability of silyl groups towards acids, bases, and fluoride ions can be specifically tuned by varying the substituents on silicon. Here are indicated the relative rates of hydrolysis of various silyl ethers under acidic and basic conditions. The order of the cleavage rates on treatment with fluoride ions is similar. ACIDOLYSIS R3Si: Me3Si < Et3Si < tBuMe2Si < iPr3Si < tBuPh2Si 1 64 2 x 104 7 x 105 5 x 106 BASIC SOLVOLYSIS R3Si: Me3Si < Et3Si < tBuMe2Si = tBuPh2Si < iPr3Si 1 10 – 100 2 x 104 2 x 104 1 x 105

7. THE EARLIEST POSSIBLE UNIFICATION OF A PROTECTING GROUP PATTERN THE USE OF PROTECTING GROUPS TO DIRECT REACTIONS THE INTRODUCTION OF "STAND-INS" AUXILIARY STRATEGIES

8. The use of protecting groups to direct reactions • The ability (or lack of) of a protecting function to complex metal ions can be utilized to direct the stereochemical course of a reaction. This use of chelating protecting groups is one of the best established tools of asymmetric synthesis BOM, MOM, and MEM ethers are typically used as chelating protecting groups. For example, here is showed the directing effect of a MEM group for the stereoselective construction of a precursor to maytansin.

9. The introduction of "stand-ins" • In the synthesis of polyfunctional compounds, two factors can make the choice of protecting group strategy particularly difficult: the lability of the intermediates and the fact that sufficiently different enough protecting groups might not be available for a given type of functional group. • In one increasingly popular alternative strategy a “stand-in” is introduced for the required functional group. In the case of a carbonyl group, a masked alcohol can be used, which can be deprotected and subsequently oxidized to give the required aldehyde or ketone. Although a further protecting group must be introduced in following this strategy, many more masking groups are established for the hydroxyl function.

10. Unification of Protecting Groups • In the construction of polyfunctional molecules the tactic of drastically different reaction conditions can lead to problems in the late stages of a synthesis, for example after successful construction of the molecular framework. • First, the molecule must be stable under all of the conditions used for deblocking. This stipulation must be made in the selection of protecting groups for each subunit in the whole molecule. It is thus possible that only a few - and under certain circumstances too few - of the available protecting groups fulfill this criterium. • Second, such a strategy can lead to a significant increase in the number of steps required at the end of the synthesis, even to the point that the associated losses become crippling.

11. To avoid these problems, the following strategy is often followed, in particular in complex multistep syntheses. As early as possible in the synthesis, protecting groups are used that can be removed under the same conditions in order to unify the protecting group pattern as much as possible. • For example, intermediates having a single type of protecting group can be designed and used from the beginning of a synthesis, thus automatically simplifying the problem. • This strategy cannot be used if specific reactivities in the intermediates are eliminated in the course of the synthesis, or the directing effect of particular protecting groups is required. Then protecting groups in the intermediates must be removed and replaced with others that correspond to the type remaining in the molecule. Under certain conditions this can increase the length of the synthesis; however, the risk of losses is shifted toward earlier stages in the synthesis with the simpler and more readily available early intermediates.

12. Protecting Groups with Modulated Lability Protecting groups with modulated lability are often utilized in organic synthesis, although they do not provide the same degree of safety offered by orthogonally stable functions. In particular, this strategy is applied when several of the same type of functional group are present in the molecule to be protected for which an insufficient number of orthogonal groups is available, or when the removal of the most stable protecting group could lead to undesired side reactions.

13. Modulated Acid- or Base-Lability In many cases acetals have different labilities towards acids. For instance, acyclic acetals are more sensitive than their cyclic equivalents to acidic conditions. This property was utilized in the synthesis of a prostaglandin precursor.