Multi step synthesis

Protective groups
Hydroxyl
Amino
Carbonyl and
Carboxylic acid groups
Synthetic equivalents
Control of stereochemistry.
 Protective groups

• When planning and executing multistep synthesis involving

15-20 or more steps, an important consideration is the
compatibility of the functional groups that are already present
with the reaction conditions required for subsequent steps.
• It is frequently necessary to modify this functional group to
prevent some interference with some reaction in the
synthetic sequence.
• One way to do this is to use protective groups.
• A protective group is a derivative that can be put in place and
then removed after the required reaction is completed.
Several other synthetic equivalents have been developed. Eg
Dienophiles with masked functionality – Cyclo addition
 Diel’s Alder reactions

Diene Dienophile
 Dienophiles that contain masked functionality and are the synthetic equivalent of
unreactive or inaccessible species.

 -chloroacrylonitrile shows satisfactory reactivity as a dienophile.

 The -chloronitrile functionality in the adduct can be hydrolyzed to a carbonyl group, so

-chloroacrylonitrile can function as the equivalent of ketene, CH2=C=O

 Ketene itself is not a suitable dienophile because it reacts with dienes by [2+2]
cycloaddition, rather than in the desired [4+2] fashion
 Nitroalkenes are good dienophiles

 Nitro groups can be converted to carbonyl groups by reductive hydrolysis, so

nitroethene can also be used as a ketene equivalent
 Vinyl sulfones are useful dienophiles.

 The sulfonyl group can be removed reductively with sodium amalgam. In this two-step
reaction sequence, the vinyl sulfone functions as an ethene equivalent.

 The sulfonyl group also allows for alkylation of the adduct, via the carbanion.

 This three-step sequence permits the vinyl sulfone to serve as the synthetic equivalent of a
terminal alkene
Acid-catalysed dehydration of alcohols and other E1 eliminations, as
well as eliminations from alkyl halides and sulfonates with base, give the
more highly substituted alkene as the major product (the Saytzeff or
Zaitsev rule),

whereas base induced eliminations from quaternary ammonium salts

and from sulfonium salts give predominantly the less-substituted alkene
(the Hofmann rule)
42
 Enantioselective Diels-Alder Reactions
 The highly ordered cyclic TS of the Diels-Alder reaction permits design of reactants and
catalysts that lead to a preference between diastereomeric or enantiomeric adducts

 One way to achieve diastereoselectivity is to install a chiral auxiliary.

 The cycloaddition proceeds to give two diastereomeric products that can be separated and
purified.

 Because of the lower temperature and the greater stereoselectivity, the best
diastereoselectivity is often observed in Lewis acid–catalyzed reactions.
Chiral esters and amides of acrylic acid are particularly useful because
the chiral auxiliary can be easily recovered by hydrolysis of the
purified adduct to give the enantiomerically pure carboxylic acid
Prediction and analysis of diastereoselectivity is based on steric, stereoelectronic, and chelating
interactions in the TS. For example, the facial selectivity of the reaction above is governed by a
chloride ligand on titanium, which shields one face of the dienophile
2- Butanone has enantiotopic faces Enantiotopicfaces are called prochiral faces

The chiral enzyme catalyst controls the stereochemistry of the reaction giving only the
R -2- butanol while by catalytic hydrogenation there is no control in the
stereochemistry of the reaction ; a racemic mixture (R and S) is formed