Protecting groups for the amino group

1. Protecting groups for the amino group Why must an amino group be protected? because it can contain acid protons it can be deprotonated by strong bases because it is a nucleophilic site it reacts with electrophiles The most general way of masking nucleophilicity is by acylation.

2. Protection of amino groups as carbamates 1) Carbobenzoxy group (CBz). The most widely used group is the carbobenzyloxygroup (Cbz). PROTECTION: DEPROTECTION: Because of the lability of the benzyl bond toward hydrogenolysis, the amine can be regenerated from a Cbz derivative by hydrogenolysis, which is accompanied by spontaneous decarboxylation of the resulting carbamic acid.

3. Protection of amino groups as carbamates 2) t-Butoxycarbonyl (t-Boc) PROTECTION: DEPROTECTION: CF3COOH, p-toluensulfonic acid

4. PROTECTION: formation of the amide starting from the corresponding acyl chloride or anhydride DEPROTECTION: the use of these amides is characterized by the possibility of a cleavage in mild conditions Protection of amino groups as amides a) phtalimides

5. b) trifluoroacetamides mild basic hydrolysis b) trichloroacetamides, benzamides partial reduction

6. b) sulphonamides photochemical cleavage 3) Allyloxy group The allyloxy group is removed by Pd-catalyzed reduction or nucleophilic substitution. These reactions involve liberation of the carbamic acid by oxidative addition to the palladium. The allyl-palladium species is reductively cleaved by stannanes, phenylsilane, formic acid and NaBH4.

7. Carbamic acid is removed by oxidative addition to palladium. The allylpalladium is then reductively cleaved by stannane

8. Protecting groups for the carbonyl group Why must a carbonyl group be protected? because it can be reduced it reacts with reducing agents because it is an electrophilic site it reacts with nucleophiles

9. acid catalysed exchange with a ketal Protection of carbonyl groups as acetals and thioacetals PROTECTION: acid catalysed formation of acetals • The carbonyl group can be deprotected by acid-catalyzed hydrolysis by the general mechanism for acetal hydrolysis • LiBF4/CH3CN DEPROTECTION:

10. b) non hydrolityc conditions (b-haloalcohols) PROTECTION: DEPROTECTION (b-elimination):

11. c) non-acid conditions PROTECTION: DEPROTECTION:

12. Protecting groups for the carboxyl group The carbonyl group can be protected in several ways The hydroxy group is generally protected as t-buthyl ester, that allows cleavage in acid conditions, or as 2,2,2-trichloroethyl ester, that can be cleaved in reductive conditions with Zn

13. PROTECTION: a) oxazolidines DEPROTECTION: The carboxylic acid group can be regenerated by acidic hydrolysis or converted to an ester by acid-catalyzed reaction with the appropriate alcohol.

14. a) ortho esters. Ortho esters derived from simple alcohols are very easily hydrolyzed, and a more useful ortho ester protecting group is the 4-methyl-2,6,7-trioxabicyclo[2.2.2]octane structure. These bicyclic orthoesters can be prepared by exchange with other ortho esters, by reaction with iminoethers, or by rearrangement of the ester derived from 3-hydroxymethyl-3-methyloxetan. exchange rearrangement

15. a) cyclic b) acyclic Protection of ester groups • In general, the methods for protection and deprotection of carboxylic acids and esters are not as convenient as those for alcohols, aldehydes, and ketones. • It is, therefore, common to carry potential carboxylic acids through synthetic schemes in the form of protected primary alcohols or aldehydes. • The carboxylic acid can then be formed at a late stage in the synthesis by an appropriate oxidation. • This strategy allows one to utilize the wider variety of alcohol and aldehyde protective groups indirectly for carboxylic acid protection.