Chapter 13.
Planning and Execution of
Multistep Synthesis
Introduction
Protective groups are used to temporarily modify functionality, which is then
restored when the protecting group is removed.
Synthetic equivalent group is an alternative structure that can subsequently be
converted to the desired group.
Protective groups and synthetic equivalent groups are tactical tools of mutistep
synthesis.
Synthetic plan is normally created on the basis of retrosynthetic analysis, which
involves the identification of the particular bonds that need to be formed to
obatin the desired molecule.
Most synthetic plans involve a combination of linear sequences and convergent
steps. Linear sequences transform the starting material step-by-step by
incremental transformations. Convergent steps bring together fragments of the
molecule, which have been created by linear sequences.
13.1 Protective Groups
The use of the silyl group replaces the hydroxyl group with a less nucleophilic
and aprotic ether. The acetal group prevents both unwanted nucleophilic
addition and enolate formation at an aldehyde site.
It is desirable to minimize the number of operations for the protective group
introduction and removal.
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
(3) the conditions that can be tolerated for removal of the protective group
No universal protective groups exist.
13.1.1. Hydroxyl-Protective Groups
A common requirement in synthesis is that a hydroxyl group be masked as
a derivative lacking a hydroxylic proton. An example of this requirement is
in reactions involving Grignard or other organometallic reagents.
Conversion to an alkyl or silyl ehter is the most common means of protecting
hydroxyl group.
(THP; tetrahydropyranyl
ether)
Mildly acidic hydrolysis is an appropriate method for deprotection
(dilute aqueous acid)
THP group is introduced by an acid-catalyzed addition of the alcohol to the
vinyl ether in dihydropyran. (catalyst: p-toluenesulfonic acid or its pyridinium salt)
THP group: inert to nucleophilic reagent and unchanged under hydride reduction,
organometallic reactions, oxidation, or base-catalyzed reactions in aqueous
solution,
Disadvantage: a stereogenic center is produced at C-2 of the THP ring.
If the alcohol is chiral, the reaction will give a mixture of diastereomeric ethers,
which may complicate purification and characterization.
To overcome THP disadvantage, methyl 2-propenyl ether is used.
There is no chiral center and it can be hydrolyzed under somewhat milder
conditions than those required for THP ethers.
The methoxymethyl (MOM) and b-methoxyethoxymethyl (MEM) groups are
used to protect alcohols and phenols as formaldehyde acetals.
Alkali metal salt
of aldohol
MEM group: can be removed under nonaquesous conditions. Lewis acid
such as zinc bromide, magnesium bromide, titanium tetrachloride, dimethyl
boron bromide, and trimethylsilyl iodide permits its removal. The MEM group
is cleaved in preference to the MOM or THP groups under these conditions.
Conversely, the MEM group is more stable to acidic aqueous hydrolysis than
the THP group.
Simple alkyls are generally not very useful for protection of alcohols as ethers.
But t-butyl group is an exception and has found some use as a hydroxyprotecting group. Because of the stability of the t-butyl cation, t-butyl ethers
can be cleaved under moderately acidic conditions: trifluoroacetic acid. And
t-butyl group is normally introduced by reaction of the alcohol with isobutylene
in the presence of an acid catalyst.
The triphenylmethyl (trityl, Tr) group is removed under even milder conditions than
the t-butyl group and is an important hydroxy-protecting group, especially in
carbohydrate chemistry.
The benzyl group can serve as a hydroxy-protecting group when acidic conditions
for ether cleavage cannot be tolerated. The benzyl C-O is cleaved by catalytic
hydrogenolysis or by electron-transfer reduction using sodium in liquid ammonia
or aromatic radical anions.
Allyl ethers can be cleaved by conversion to propenyl ethers, followed by acidic
hydrolysis of the enol ether.
The isomerization of an allyl ether to a propenyl ether can be achieved either by
treatment with potassium t-butoxide in DMSO or by Wilkinson’s catalyst or
(PPh3)3RhH. Heating allyl ethers with Pd/C in acidic methanol can also effect
cleavage.
Silyl ether plays a very important role as hydroxy-protecting groups. Alcohol
can be easily converted to trimethylsilyl (TMS) ethers by reaction with
trimethylsilyl chloride in the presence of an amine or by heating with
hexamethyldisilazane. t-Butyldimethylsilyl (TBDMS) ethers are also very
useful. The increased steric bulk of the TBDMS group improve the stability of
the group toward such reactions as hydride reduction and Cr(VI) oxidation.
Cleavage of the TBDMS group is slow under hydrolytic conditions, but anhydrous
tetra-n-butylammonium fluoride, methanolic NH4F, aquesous HF, etc can be
used for its removal.
Hydrolytic stability of the various silyl protecting groups is TMS<TBDMS<
TIPS (isopropyl)<TBDPS (tributyldiphenylsilyl). All the groups are susceptible
to TBAF cleavage, but the TPS and TBDPS groups are cleaved more slowly
than the trialkylsilyl groups.
1,2- and 1,3-diols easily form acetals with aldehyde and ketone.
isopropylidene group
Acid-catalyzed exchange with 2,2-dimethoxypropane
This ketal protecting group is resistant to basic and nucleophilic reagents but
is readily removed by aqueous acid.
Protection of an alcohol function by esterification sometimes offers advantages
over use of acetal or ether groups. Generally, ester groups are stable under
acidic conditions. Esters are especially useful in protection during oxidations.
Imidazolies are less reactive than the corresponding acyl chloride and can
exhibit a higher degree of selectivity in reactions with a molecules possessing
several hydroxyl groups.
Ester groups can be removed readily by base-catalyzed hydrolysis. When
basic hydrolysis is inappropriate, special acyl groups are required. Trichloroethyl
carbonate ester can be reductively removed with zinc.
Allyl carbonate esters are also useful hydroxyl-protecting groups.
Nucleophile: dimedone, pentane-2,4-dione, amines
13.2.3. Amino-Protecting Groups
Primary and secondary amino groups are nucleophilic and easily oxidized. If
either of these types of reactivity will cause a problem, the amino group must
be protected. The most general way of masking nucleophilicity is by acylatgion.
Carbamates are particularly useful. The most widely used group is the
carbobenzyloxy (Cbz)group.
Hydrogenolysis
carbamates
Carbamic acid
Deprotection: hydrogenolysis, methods to tranfer hydrogenolysis using
hydrogen donors such as ammonium formate or formic acid with Pd/C catalyst
The t-butoxycarbonyl (t-Boc) group is another valuable amino-protecting group.
The removal in this case is done with an acid such as trifluoroacetic acid or
p-toluenesulfonic acid. t-Butoxycarbonyl groups are introduced by reaction of
amines with t-butoxypyrocarbonate or the mixed carbonate ester known as
“BOC-ON”
Allyl carbamates can also serve as amino-protecting groups. The allyloxy
group is removed by Pd-catalyzed reduction or nucleophilic substitution.
Phthalimides are used to protect primary amino group. The phthalimides can
be cleaved by treatment with hydrazine.
Reduction by NaBH4 in aqueous ethanol is an alternative method for
deprotection of phthalimides.
Because of the strong electron-withdrawing effect of the triflouromethyl group,
trifluoroacetamides are subject to hydrolysis under mild conditions.
The 4-pentenoyl group is easily removed from amides by I2 and can be used
as a protective group. The mechanism of cleavage involves iodocyclization and
hydrolysis of the resulting iminolactone.
13.1.3. Carbonyl-Protecting Groups
Ethylene glycol, which gives a dioxolane derivatives, is frequently employed
for carbonyl protection under acid catalyst.
Azeoptropic
distillation
Ketal can be prepared by acid-catalyzed exchange with a ketal such
as 2,2-dimethoxypropane or an ortho ester.
If the carbonyl group must be regenerated under nonhydrolytic conditions,
b-halo alcohols such as 3-bromo-1,2-dihydroxypropane or 2,2,2-triochloro
propane can be used for acetal formation. These groups can be removed by
reducdion with zinc, which proceeds with b-elimination.
13.1.4. Carbxylic Acid-Protecting Groups
If only the O-H, as opposed to the carbonyl, of a carboxyl group needs to
be masked, this can be readily accomplished by esterification. Alkaline
hydrolysis is the usual way of regenerating the acid. t-Butyl esters, which
are readily cleaved by acid, can be used if alkaline conditions must be avoided.
Oxazoline derivative
Heterocyclic derivative successfully protects the acids from attack by Grignard
reagents or hydride-transfer reagents.
The carboxylic acid group can be regenerated by acidic hydrolysis or converted
to an ester by acid-catalyzed reaction with the appropriate alcohol.
Carboxylic acid can also be protected as ortho esters.
Lactones and acyclic esters can be protected as their dithioketals by using a
method that is analogous to ketone protection.
In general, the methods for protection and deprotection of carboxylic acids
and esters are not as convenient as those for alcohols, aldehydes and
ketones. So, the carboxylic acid can then be formed at a late stage in the
synthesis by an appropriate oxidation.
13.2 Synthetic Equivalent Groups
It is often advantageous to combine the need for masking of a functional
group with a change in the reactivity of the functionality in question.
The masked functionality used in place to an inaccessible species in termed
a synthetic equivalent group. Often, the concept of “umpolung” is involved
in devising synthetic equivalent groups. The term “umpolung” refers to the
reversal of the normal polarity of a functional group. The acyl anion equivalent
would be an umpolung of the acyl group.
O
O
O
O
O
+
OH
O
X
-X
O
O
-H
HO
O
O
O
O
O
O
+
OH
O
O
HO
O
O
O
O
O
+
S
Li
O
Umpolung
(polarity reversal)
O
O
S
?
O
O
+
O
O
?
X
a-Lithio vinyl ethers provide acyl anion equivalents.
Sulfur compounds have also proven to be useful as nucleophilic acyl equivalents.
1,3-Dithiane
a-alkylthiosulfoxide
Acyl anion equivalents
Homoenolate
-CH CH CH=O
2
2
All deliver the aldehyde functionality in a masked form, such as an acetal
or enol ether. The aldehyde must be liberated in a final step from the
protected precursor.
B and C incorporated both electrophilic and nucleophilic centers. Such
reagents might be incorporated into ring-forming schemes, because they
have the ability, at least formally, of undergoing cycloaddition reactions.
13.3. Synthetic Analysis and Planning
In this chapter. Tactical tools of synthesis such as protective groups and
synthetic equivalent groups have been introduced.
In general, a large number of syntheses of any given compound are possible.
The initial step in creating a synthetic plan should involve a retrpsynthetic
analysis. The structure of the molecule is dissected step-by-step along
reasonable pathway successively simpler compounds until molecules that
are acceptable as starting materials are reached.
Bond Disconnection  key intermediate
Antisynthetic transforms (retrosynthesis) reverse of synthetic steps
The purpose of making a synthesis more convergent is to decrease its overall
length.
Overall yields decrease with the increase in number of steps to which the original
starting material is subjected.
It is frequently necessary to interconvert functional groups.
Protective groups and synthetic equivalent groups are important for planning
to functional group transformations.
Even with the best of planning, unexpected problems are frequently encountered.
13.4 Control of Stereochemistry
The number of possible stereoisomers is 2n, where n is the number of
stereogenic centers.
Four general approaches that are used to obtain enantiomerically pure
material by synthesis.
1) incorporating a resolution of racemic mixtures
2) Using a starting material that is enantiomerically pure
3) Use of a stoichiometric amount of a chiral auxiliary
4) Use a chiral catalyst in a reaction which creates one or more stereocenters.
Ranking of approaches
Resolution < natural source < chiral auxiliary < enantioselective catalyst
100% efficiency
reused
limited amount
50% used
not reused
stoichiometric amount
13.5 Illustrative Syntheses
Juvabione is terpene-derived keto ester that has been isolated from various
plant sources. It exhibits “juvenile hormone” activity in insects; that is, it
can modify the process of metamorphosis.