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Chimie organique Chapitre CO / PC-‐2 : Protection de groupes en chimie organique
Cours de chimie de seconde période de PCSI Option PC
2
PCSI-‐option PC
Protection de groupe
I-‐ POURQUOI PROTEGER ? 3
II-‐ PROTECTION DU GROUPE CARBONYLE 3 1. PREMIER EXEMPLE : PROTECTION PAR PASSAGE A L’ACETAL 3 2. AUTRE EXEMPLE D’UNE PROTECTION PAR PASSAGE A L’ACETAL 5 3. UNE VARIANTE : PROTECTION PAR UN ANALOGUE SOUFRE 7
III-‐ PROTECTION DU GROUPE HYDROXYLE 8 1. PASSAGE A L’ETHEROXYDE 8 2. EXEMPLES 8
2.1. UN PHENOL PHOH SERA PROTEGE EN UTILISANT CH3BR OU CH3I 8 2.2. UN DIOL VICINAL SERA PROTEGE PAR LA PROPANONE 9 2.3. UN ALCOOL POURRA ETRE PROTEGE DE PLUSIEURS FAÇONS DIFFERENTES. 11
2.3.1. par une synthèse de Wiliamson, comme les phénols 11 2.3.2. par passage à un éther tertiobutylique 12 2.3.3. en utilisant le chlorure de benzyle 12 2.3.4. en utilisant les éthers silylés 13
IV FAUT-‐IL TOUJOURS PROTEGER ? 14
Le Plan du cours
3
I-‐ Pourquoi protéger ?
Le but d’une protection est de préserver un groupe caractéristique intact. Ainsi, en protégeant ce groupe, on le préserve en l’empêchant de réagir. Le groupe n’est donc plus le groupe caractéristique initial et il ne réagit donc plus de la même façon vis-‐à-‐vis des différents réactifs. Il est alors possible de protéger une fonction réactive de façon de faire de nombreuses étapes d’aménagement fonctionnel sur d’autres parties de la molécule. Puis, lors d’une ultime étape de déprotection on récupère la fonction protégée précédemment. Il apparaît alors que : Les étapes de protection et de déprotection sont des étapes qui doivent se faire avec des rendements proches de 100% L’objectif étant de protéger une partie de la molécule mais de la récupérer intégralement à l’issue des transformations effectuées. Protéger un groupe devient nécessaire lorsque le réactif peut réagir sur deux groupes caractéristiques d’une molécule : ce réactif n’est pas chimiosélectif. Illustrons cette nécessité de protection dans deux cas courants :
la protection du groupe carbonyle, la protection du groupe hydroxyle.
II-‐ Protection du groupe carbonyle 1. Premier exemple : protection par passage à l’acétal
Sur l’exemple ci-‐dessus, nous souhaitons que le bromure de phénylmagnésium réagisse réagir sur la fonction ester (cette réaction n’est pas au programme mais retenons qu’un
Although anions can often be formed straightforwardly next to alkynes, there are two othermore acidic protons (green) in the molecule that would be removed by base before the yellowproton. However, treatment with three equivalents of butyl lithium removes all three, and thetrianion reacts with ethylene oxide at the last-formed anionic centre to give the required com-pound.
How to react the less reactive group (II): protecting groupsThe usual way of reacting a less reactive group in the presence of a more reactive one is to use a pro-tecting group. This tertiary alcohol, for example, could be made from a keto-ester if we could getphenylmagnesium bromide to react with the ester rather than with the ketone.
As you would expect, simply adding phenylmagnesium bromide to ethyl acetoacetate leads main-ly to addition to the more electrophilic ketone.
One way of making the alcohol we want is to protect the ketone as an acetal. An acetal-protectinggroup (shown in black) is used.
The first step puts the protecting group on to the (more electrophilic) ketone carbonyl, making itno longer reactive towards nucleophilic addition. The Grignard then adds to the ester, and finally a‘deprotection’ step, acid-catalysed hydrolysis of the acetal, gives us back the ketone. An acetal is anideal choice here—acetals are stable to base (the conditions of the reaction we want to do), but arereadily cleaved in acid.
By protecting sensitive functional groups like ketones it becomes possible to make reagents thatwould otherwise be unstable. In a synthesis of the natural product porantherine, a compound basedon this structure was needed.
632 24 . Chemoselectivity: selective reactions and protection
HH
H
H
HH
Li
Li
OOH
HLi
Li
Li
2 equivs BuLi BuLi
2. H
1.
O
OEt
O O OH
PhPh
PhMgBrmust react here
must not react here
O
OEt
O OH
OEt
O
Ph
52% yieldPhMgBr
!Five-membered cyclic acetals like theseare known as dioxolanes. You metthem first in Chapter 14 when we werediscussing acetal formation andhydrolysis.
O
OEt
O O OH
PhPhOEt
OOOOHHO
Ph
OHOO
Ph
2 × PhMgBr
H+
H+, H2O
!This table of protecting groupswill grow, line by line, as we movethrough this chapter and the next.
Protecting group Structure Protects From Protection Deprotection
acetal ketones, nucleophiles, water, H+ cat.(dioxolane) aldehydes bases
R R
OO HOOH
O OOH
MgBr
O
H OEt
Ofrom
impossible Grignard reagent
plus
site le plus
réactif
site le moins réactif
4
organomagnésien en excès transforme l’ester en alcool). Mais le groupe carbonyle de la fonction cétone est plus réactif :
(sous entendu ici : on utilise 1 seul équivalent de PhMgBr)
Il faut donc protéger le groupe carbonyle de cette fonction cétone afin de le protéger et de ne rendre « invisible » vis à vis de l’organomagnésien : la méthode privilégiée consiste à la formation d’un acétal et la séquence sera donc la suivante : Protection du groupe carbonyle :
rendement : 52 %
Although anions can often be formed straightforwardly next to alkynes, there are two othermore acidic protons (green) in the molecule that would be removed by base before the yellowproton. However, treatment with three equivalents of butyl lithium removes all three, and thetrianion reacts with ethylene oxide at the last-formed anionic centre to give the required com-pound.
How to react the less reactive group (II): protecting groupsThe usual way of reacting a less reactive group in the presence of a more reactive one is to use a pro-tecting group. This tertiary alcohol, for example, could be made from a keto-ester if we could getphenylmagnesium bromide to react with the ester rather than with the ketone.
As you would expect, simply adding phenylmagnesium bromide to ethyl acetoacetate leads main-ly to addition to the more electrophilic ketone.
One way of making the alcohol we want is to protect the ketone as an acetal. An acetal-protectinggroup (shown in black) is used.
The first step puts the protecting group on to the (more electrophilic) ketone carbonyl, making itno longer reactive towards nucleophilic addition. The Grignard then adds to the ester, and finally a‘deprotection’ step, acid-catalysed hydrolysis of the acetal, gives us back the ketone. An acetal is anideal choice here—acetals are stable to base (the conditions of the reaction we want to do), but arereadily cleaved in acid.
By protecting sensitive functional groups like ketones it becomes possible to make reagents thatwould otherwise be unstable. In a synthesis of the natural product porantherine, a compound basedon this structure was needed.
632 24 . Chemoselectivity: selective reactions and protection
HH
H
H
HH
Li
Li
OOH
HLi
Li
Li
2 equivs BuLi BuLi
2. H
1.
O
OEt
O O OH
PhPh
PhMgBrmust react here
must not react here
O
OEt
O OH
OEt
O
Ph
52% yieldPhMgBr
!Five-membered cyclic acetals like theseare known as dioxolanes. You metthem first in Chapter 14 when we werediscussing acetal formation andhydrolysis.
O
OEt
O O OH
PhPhOEt
OOOOHHO
Ph
OHOO
Ph
2 × PhMgBr
H+
H+, H2O
!This table of protecting groupswill grow, line by line, as we movethrough this chapter and the next.
Protecting group Structure Protects From Protection Deprotection
acetal ketones, nucleophiles, water, H+ cat.(dioxolane) aldehydes bases
R R
OO HOOH
O OOH
MgBr
O
H OEt
Ofrom
impossible Grignard reagent
plus
Although anions can often be formed straightforwardly next to alkynes, there are two othermore acidic protons (green) in the molecule that would be removed by base before the yellowproton. However, treatment with three equivalents of butyl lithium removes all three, and thetrianion reacts with ethylene oxide at the last-formed anionic centre to give the required com-pound.
How to react the less reactive group (II): protecting groupsThe usual way of reacting a less reactive group in the presence of a more reactive one is to use a pro-tecting group. This tertiary alcohol, for example, could be made from a keto-ester if we could getphenylmagnesium bromide to react with the ester rather than with the ketone.
As you would expect, simply adding phenylmagnesium bromide to ethyl acetoacetate leads main-ly to addition to the more electrophilic ketone.
One way of making the alcohol we want is to protect the ketone as an acetal. An acetal-protectinggroup (shown in black) is used.
The first step puts the protecting group on to the (more electrophilic) ketone carbonyl, making itno longer reactive towards nucleophilic addition. The Grignard then adds to the ester, and finally a‘deprotection’ step, acid-catalysed hydrolysis of the acetal, gives us back the ketone. An acetal is anideal choice here—acetals are stable to base (the conditions of the reaction we want to do), but arereadily cleaved in acid.
By protecting sensitive functional groups like ketones it becomes possible to make reagents thatwould otherwise be unstable. In a synthesis of the natural product porantherine, a compound basedon this structure was needed.
632 24 . Chemoselectivity: selective reactions and protection
HH
H
H
HH
Li
Li
OOH
HLi
Li
Li
2 equivs BuLi BuLi
2. H
1.
O
OEt
O O OH
PhPh
PhMgBrmust react here
must not react here
O
OEt
O OH
OEt
O
Ph
52% yieldPhMgBr
!Five-membered cyclic acetals like theseare known as dioxolanes. You metthem first in Chapter 14 when we werediscussing acetal formation andhydrolysis.
O
OEt
O O OH
PhPhOEt
OOOOHHO
Ph
OHOO
Ph
2 × PhMgBr
H+
H+, H2O
!This table of protecting groupswill grow, line by line, as we movethrough this chapter and the next.
Protecting group Structure Protects From Protection Deprotection
acetal ketones, nucleophiles, water, H+ cat.(dioxolane) aldehydes bases
R R
OO HOOH
O OOH
MgBr
O
H OEt
Ofrom
impossible Grignard reagent
plus
5
Addition nucléophile de l’organomagnésien, qui ne voit donc que la fonction ester, puis hydrolyse modéré (milieu pas trop acide, l’acétal est stable) :
Déprotection . En fin de réaction, l’acétal, qui est stable en milieu basique mais pas en milieu acide est hydrolysé, la fonction cétone réapparaît.
2. Autre exemple d’une protection par passage à l’acétal Par exemple : quelle stratégie de synthèse adoptée pour cette synthèse, où la molécule ci-‐dessous intervient dans la synthèse d’une molécule plus complexe, la poranthérine ?
On peut penser à l’action d’un organomagnésien sur un ester :
Rem : pourquoi ne peut-‐on pas préparer cet organomagnésien ?
Although anions can often be formed straightforwardly next to alkynes, there are two othermore acidic protons (green) in the molecule that would be removed by base before the yellowproton. However, treatment with three equivalents of butyl lithium removes all three, and thetrianion reacts with ethylene oxide at the last-formed anionic centre to give the required com-pound.
How to react the less reactive group (II): protecting groupsThe usual way of reacting a less reactive group in the presence of a more reactive one is to use a pro-tecting group. This tertiary alcohol, for example, could be made from a keto-ester if we could getphenylmagnesium bromide to react with the ester rather than with the ketone.
As you would expect, simply adding phenylmagnesium bromide to ethyl acetoacetate leads main-ly to addition to the more electrophilic ketone.
One way of making the alcohol we want is to protect the ketone as an acetal. An acetal-protectinggroup (shown in black) is used.
The first step puts the protecting group on to the (more electrophilic) ketone carbonyl, making itno longer reactive towards nucleophilic addition. The Grignard then adds to the ester, and finally a‘deprotection’ step, acid-catalysed hydrolysis of the acetal, gives us back the ketone. An acetal is anideal choice here—acetals are stable to base (the conditions of the reaction we want to do), but arereadily cleaved in acid.
By protecting sensitive functional groups like ketones it becomes possible to make reagents thatwould otherwise be unstable. In a synthesis of the natural product porantherine, a compound basedon this structure was needed.
632 24 . Chemoselectivity: selective reactions and protection
HH
H
H
HH
Li
Li
OOH
HLi
Li
Li
2 equivs BuLi BuLi
2. H
1.
O
OEt
O O OH
PhPh
PhMgBrmust react here
must not react here
O
OEt
O OH
OEt
O
Ph
52% yieldPhMgBr
!Five-membered cyclic acetals like theseare known as dioxolanes. You metthem first in Chapter 14 when we werediscussing acetal formation andhydrolysis.
O
OEt
O O OH
PhPhOEt
OOOOHHO
Ph
OHOO
Ph
2 × PhMgBr
H+
H+, H2O
!This table of protecting groupswill grow, line by line, as we movethrough this chapter and the next.
Protecting group Structure Protects From Protection Deprotection
acetal ketones, nucleophiles, water, H+ cat.(dioxolane) aldehydes bases
R R
OO HOOH
O OOH
MgBr
O
H OEt
Ofrom
impossible Grignard reagent
plus
Although anions can often be formed straightforwardly next to alkynes, there are two othermore acidic protons (green) in the molecule that would be removed by base before the yellowproton. However, treatment with three equivalents of butyl lithium removes all three, and thetrianion reacts with ethylene oxide at the last-formed anionic centre to give the required com-pound.
How to react the less reactive group (II): protecting groupsThe usual way of reacting a less reactive group in the presence of a more reactive one is to use a pro-tecting group. This tertiary alcohol, for example, could be made from a keto-ester if we could getphenylmagnesium bromide to react with the ester rather than with the ketone.
As you would expect, simply adding phenylmagnesium bromide to ethyl acetoacetate leads main-ly to addition to the more electrophilic ketone.
One way of making the alcohol we want is to protect the ketone as an acetal. An acetal-protectinggroup (shown in black) is used.
The first step puts the protecting group on to the (more electrophilic) ketone carbonyl, making itno longer reactive towards nucleophilic addition. The Grignard then adds to the ester, and finally a‘deprotection’ step, acid-catalysed hydrolysis of the acetal, gives us back the ketone. An acetal is anideal choice here—acetals are stable to base (the conditions of the reaction we want to do), but arereadily cleaved in acid.
By protecting sensitive functional groups like ketones it becomes possible to make reagents thatwould otherwise be unstable. In a synthesis of the natural product porantherine, a compound basedon this structure was needed.
632 24 . Chemoselectivity: selective reactions and protection
HH
H
H
HH
Li
Li
OOH
HLi
Li
Li
2 equivs BuLi BuLi
2. H
1.
O
OEt
O O OH
PhPh
PhMgBrmust react here
must not react here
O
OEt
O OH
OEt
O
Ph
52% yieldPhMgBr
!Five-membered cyclic acetals like theseare known as dioxolanes. You metthem first in Chapter 14 when we werediscussing acetal formation andhydrolysis.
O
OEt
O O OH
PhPhOEt
OOOOHHO
Ph
OHOO
Ph
2 × PhMgBr
H+
H+, H2O
!This table of protecting groupswill grow, line by line, as we movethrough this chapter and the next.
Protecting group Structure Protects From Protection Deprotection
acetal ketones, nucleophiles, water, H+ cat.(dioxolane) aldehydes bases
R R
OO HOOH
O OOH
MgBr
O
H OEt
Ofrom
impossible Grignard reagent
plus
Although anions can often be formed straightforwardly next to alkynes, there are two othermore acidic protons (green) in the molecule that would be removed by base before the yellowproton. However, treatment with three equivalents of butyl lithium removes all three, and thetrianion reacts with ethylene oxide at the last-formed anionic centre to give the required com-pound.
How to react the less reactive group (II): protecting groupsThe usual way of reacting a less reactive group in the presence of a more reactive one is to use a pro-tecting group. This tertiary alcohol, for example, could be made from a keto-ester if we could getphenylmagnesium bromide to react with the ester rather than with the ketone.
As you would expect, simply adding phenylmagnesium bromide to ethyl acetoacetate leads main-ly to addition to the more electrophilic ketone.
One way of making the alcohol we want is to protect the ketone as an acetal. An acetal-protectinggroup (shown in black) is used.
The first step puts the protecting group on to the (more electrophilic) ketone carbonyl, making itno longer reactive towards nucleophilic addition. The Grignard then adds to the ester, and finally a‘deprotection’ step, acid-catalysed hydrolysis of the acetal, gives us back the ketone. An acetal is anideal choice here—acetals are stable to base (the conditions of the reaction we want to do), but arereadily cleaved in acid.
By protecting sensitive functional groups like ketones it becomes possible to make reagents thatwould otherwise be unstable. In a synthesis of the natural product porantherine, a compound basedon this structure was needed.
632 24 . Chemoselectivity: selective reactions and protection
HH
H
H
HH
Li
Li
OOH
HLi
Li
Li
2 equivs BuLi BuLi
2. H
1.
O
OEt
O O OH
PhPh
PhMgBrmust react here
must not react here
O
OEt
O OH
OEt
O
Ph
52% yieldPhMgBr
!Five-membered cyclic acetals like theseare known as dioxolanes. You metthem first in Chapter 14 when we werediscussing acetal formation andhydrolysis.
O
OEt
O O OH
PhPhOEt
OOOOHHO
Ph
OHOO
Ph
2 × PhMgBr
H+
H+, H2O
!This table of protecting groupswill grow, line by line, as we movethrough this chapter and the next.
Protecting group Structure Protects From Protection Deprotection
acetal ketones, nucleophiles, water, H+ cat.(dioxolane) aldehydes bases
R R
OO HOOH
O OOH
MgBr
O
H OEt
Ofrom
impossible Grignard reagent
plus
Although anions can often be formed straightforwardly next to alkynes, there are two othermore acidic protons (green) in the molecule that would be removed by base before the yellowproton. However, treatment with three equivalents of butyl lithium removes all three, and thetrianion reacts with ethylene oxide at the last-formed anionic centre to give the required com-pound.
How to react the less reactive group (II): protecting groupsThe usual way of reacting a less reactive group in the presence of a more reactive one is to use a pro-tecting group. This tertiary alcohol, for example, could be made from a keto-ester if we could getphenylmagnesium bromide to react with the ester rather than with the ketone.
As you would expect, simply adding phenylmagnesium bromide to ethyl acetoacetate leads main-ly to addition to the more electrophilic ketone.
One way of making the alcohol we want is to protect the ketone as an acetal. An acetal-protectinggroup (shown in black) is used.
The first step puts the protecting group on to the (more electrophilic) ketone carbonyl, making itno longer reactive towards nucleophilic addition. The Grignard then adds to the ester, and finally a‘deprotection’ step, acid-catalysed hydrolysis of the acetal, gives us back the ketone. An acetal is anideal choice here—acetals are stable to base (the conditions of the reaction we want to do), but arereadily cleaved in acid.
By protecting sensitive functional groups like ketones it becomes possible to make reagents thatwould otherwise be unstable. In a synthesis of the natural product porantherine, a compound basedon this structure was needed.
632 24 . Chemoselectivity: selective reactions and protection
HH
H
H
HH
Li
Li
OOH
HLi
Li
Li
2 equivs BuLi BuLi
2. H
1.
O
OEt
O O OH
PhPh
PhMgBrmust react here
must not react here
O
OEt
O OH
OEt
O
Ph
52% yieldPhMgBr
!Five-membered cyclic acetals like theseare known as dioxolanes. You metthem first in Chapter 14 when we werediscussing acetal formation andhydrolysis.
O
OEt
O O OH
PhPhOEt
OOOOHHO
Ph
OHOO
Ph
2 × PhMgBr
H+
H+, H2O
!This table of protecting groupswill grow, line by line, as we movethrough this chapter and the next.
Protecting group Structure Protects From Protection Deprotection
acetal ketones, nucleophiles, water, H+ cat.(dioxolane) aldehydes bases
R R
OO HOOH
O OOH
MgBr
O
H OEt
Ofrom
impossible Grignard reagent
plus
MAIS on ne peut pas préparer ce Grignard ...
6
Ou alors, il faut protéger la fonction carbonyle AVANT de préparer le magnésien :
Voici d’autres exemples :
One way to make it is to add a Grignard reagent twice to ethyl formate. But, of course, a ketone-containing Grignard is an impossibility as it would self-destruct, so an acetal-protected compoundwas used.
Strongly nucleophilic reagents like Grignard reagents and organolithiums are also strong bases,and may need protecting from acidic protons as well as from electrophilic carbonyl groups. Amongthe most troublesome are the protons of hydroxyl groups. When some American chemists wanted tomake the antiviral agent Brefeldin A, they needed a simple alkynol.
A synthesis could start with the same bromoketone as the one above: reduction gives an alcohol,but alkylation of an alkynyl anion with this compound is not possible, because the anion will justdeprotonate the hydroxyl group.
The answer is to protect the hydroxyl group, and the group chosen here was a silyl ether. Suchethers are made by reacting the alcohol with a trialkylsilyl chloride (here t-butyl dimethyl silylchloride, or TBDMSCl) in the presence of a weak base, usually imidazole, which also acts as anucleophilic catalyst (Chapter 12).
Silicon has a strong affinity for electronegative elements, particularly O, F, and Cl, so trialkyl-silyl ethers are attacked by hydroxide ion, water, or fluoride ion but are more stable to carbonor nitrogen bases or nucleophiles. They are usually removed with aqueous acid or fluoride salts,particularly Bu4N+F– which is soluble in organic solvents. In fact, TBDMS is one member of awhole family of trialkylsilyl protecting groups and their relative stability to nucleophiles of variouskinds is determined by the three alkyl groups carried by silicon. The most labile, trimethylsilyl(TMS), is removed simply on treatment with methanol, while the most stable require hydrofluoricacid.
One functional group may be more reactive than another 633
RO SiMe3
RO SiMe2But
O HO OHOO OO
OHOO OO
Br Br MgBr
O OOH
H cat. Mg, Et2O HCO2Et
H
H2O
OH
Br
OHO
BrLi Li
Br
OHreduce
(e.g. NaBH4)
deprotonation of hydroxyl group by strongly basic reagent
reacts here not here
NHN
(a weak base)imidazole =
Br
OH
Br
OSi
Me
Me
t-Bu
Si
Me
Me
t-Bu
ClLi OTBDMS
the TBDMS protecting group
imidazole
!Although not important to ourdiscussion here, these substitutionreactions are not the simple SN2reactions (Chapter 17) they mightappear to be. The nucleophile adds tosilicon first to form a five-valent anionwhich decomposes with the loss of thealcohol (Chapter 21).
RO
Sit-Bu
Me Me
RO
Sit-Bu
Me Me
H
H2O
ROHRO
Sit-Bu
Me Me F
ROHH3OF
(often Bu4N+F–)
Protecting group Structure Protects From Protection Deprotection
trialkylsilyl alcohols (OH nucleophiles, R3SiCl, base H+, H2O, or F–
(R3Si-, e.g. TBDMS) in general) C or N bases
Protection
Déprotection
Réaction 1 Réaction 2
3.4 Protection of Carbonyl Croups in Aldehydes and Ketones ~ 73 . ". -- . . ,...... -
Acetalization with Diols. l,3-Dioxolane (five-member ring acetal) is the most wide- ly used C=O protecting group. The formation of acetals with diols provides an entro- pic advantage over the use of two equivalents of an alcohol. The water formed is removed by azeotropic distillation.
catalysts for acetalization: PPTS, BF3 OEt2, TsOH, or amberlyst-15
cleavage of 1,3-dioxolanes: TsOH and H20, or 5% HCI in THF, or amberlyst-15 in acetone and H20
Utilization of orthoformate esters66 and ~ e , ~ i ~ l ~ ~ are standard procedures for water removal in acetalization. In the latter case, water is removed as hexarnethyldi- siloxane.
TsOH, 20 "C, 24 h (- MeOH)
0 HO(CH2)20H Me3SiCI (2.2 eq) f---l
n-C5H I I+ CH2CI2 XCO~M~ C02Me n-C5H 11
88%
Acid-catalyzed acetalization of a,/3-unsaturated ketones may result in double bond migration. The extent of migration of the double bond of enones depends on the strength of the acid catalyst ~ s e d . ' ~ , ~ ~
7
3. Une variante : protection par un analogue soufré
O
R HH+ (cat)
protection
SH SH
R H
SS
3.4 Protection of Carbonyl Croups in Aldehydes and Ketones ~ 73 . ". -- . . ,...... -
Acetalization with Diols. l,3-Dioxolane (five-member ring acetal) is the most wide- ly used C=O protecting group. The formation of acetals with diols provides an entro- pic advantage over the use of two equivalents of an alcohol. The water formed is removed by azeotropic distillation.
catalysts for acetalization: PPTS, BF3 OEt2, TsOH, or amberlyst-15
cleavage of 1,3-dioxolanes: TsOH and H20, or 5% HCI in THF, or amberlyst-15 in acetone and H20
Utilization of orthoformate esters66 and ~ e , ~ i ~ l ~ ~ are standard procedures for water removal in acetalization. In the latter case, water is removed as hexarnethyldi- siloxane.
TsOH, 20 "C, 24 h (- MeOH)
0 HO(CH2)20H Me3SiCI (2.2 eq) f---l
n-C5H I I+ CH2CI2 XCO~M~ C02Me n-C5H 11
88%
Acid-catalyzed acetalization of a,/3-unsaturated ketones may result in double bond migration. The extent of migration of the double bond of enones depends on the strength of the acid catalyst ~ s e d . ' ~ , ~ ~
8
III-‐ Protection du groupe hydroxyle 1. Passage à l’étheroxyde Les étheroxydes sont peu réactifs, et sont donc bien adaptés pour la protection du groupe OH des alcools ou phénols. Il existe une grande variété de groupements protecteurs du groupe OH, les éthers obtenus ayant des stabilités qui peuvent être différentes suivant la nature du milieu, acide ou basique. Enfin, les éthers silylés sont très couramment utilisés aussi : ce sont des éthers contenant des dérivés du silicium. 2. Exemples
2.1. Un phénol PhOH sera protégé en utilisant CH3Br ou CH3I Ci-‐dessous, le groupe hydroxyle OH doit être protégé car il possède un hydrogène mobile, susceptible de réagir avec la base très base qu’est l’ion alcynure (alcynure de sera protégé en utilisant CH3Br ou CH3I. La séquence la plus commune est la suivante : réaction acide-‐base, obtention de l’ion phénolate :
OH
+ CO32-
O
+ HCO3-
phénol phénolate
pKA = 10,0 pKA = 10,3
carbonate hydrogénocarbonate
passage à l’éther oxyde :
9
O
+ Brd+CH3 Br
SN2
OCH3
+d-
transformation de molécule initiale :
transformations
OCH3 OCH3
transformé
déprotection, régénération du groupe OH :
OCH3
transformé + HI
OH
transformé + CH3-I
2.2. Un diol vicinal sera protégé par la propanone Un diol vicinal peut servir à protéger un groupe carbonyle, et l’inverse est également vrai : un composé carbonylé peut servir de groupe protecteur pour un diol-‐1,2 ou bien un diol-‐1,3. On peut par exemple la propanone. Quoiqu’il en soit, c’est bien la réaction d’acétalisation est qui est utilisée.
OH
OH
+ O
APTS- H2O
O
O Exemple :
10
O
H
Ph OO
OHOH
OMe
O
H
Ph
OOH
OH
OHOH
OMeZnCl2
OH OH
O
CH3 CH3H+ (cat)
O O
CH3CH3
H2O / H+ (cat)
protection
deprotection
O
CH3 CH3H+ (cat)
O O
CH3CH3
H2O / H+ (cat)
protection
OHOH
deprotection
11
doubleacetalisation
hémiacetalisation
2.3. Un alcool pourra être protégé de plusieurs façons différentes.
2.3.1. par une synthèse de Wiliamson, comme les phénols Ici, contrairement au phénol, la base devra être très forte. L’ion carbonate CO32-‐ est remplacé par l’ion hydrure, base très forte
• Détail des différentes réactions mises en jeu sachant que, dans la dernière étape, TMSI désigne l’ IodoTriMéthyleSilane l’Iodure deTriMéthylSilyle :
3.2 Protect~on of OH Croups of Alcohols - 61 - -
The stability of ethers and mixed acetals as protecting groups for alcohols varies from the very stable methyl ether to the highly acid-labile trityl ether. However, all ethers are stable to basic reaction conditions. Hence, ether or mixed acetal protecting groups specifically tolerate
RMgX and RLi reagents Nucleophilic reducing reagents such as LiAlH, and NaBH, Oxidizing agents such as CrO, 2 pyridine, pyridinium chlorochromate (PCC), and MnO, Wittig reagents Strong bases such as LDA
A l b 1 Ethers Methyl Ethers 1 RO-CH, I Methyl ethers are readily accessible via the Williamson ether synthesis, but harsh con- ditions are required to deprotect them. For hindered alcohols, the methylation should be carried out in the presence of KOH/DMSO.'~
Reagents for cleaving methyl ethers include Me,SiI (or Me,SiCl -I- NaI) in C H , C ~ , ~ ~ and BBr, (or the solid BBr, SMe, complex) in CH,C~,." BBr, is especial- ly effective for cleaving PhOCH3.12
NaH TMSl ROH ROCH3 ROH
THF, 0 "C CH2CI2 (aq, acid workup)
Methylation of sec-OH groups in sugars with methyl iodide and silver oxide is often the method of choice.
ROH ROCH3 DMF
tert-Butyl Ethers 1 R O - C M ~ ~ I t-Butyl ethers are readily prepared and are stable to nucleophiles, hydrolysis under basic conditions, organometallic reagents, metal hydrides, and mild oxidations. However, they are cleaved by dilute acids (S,1 reaction).
t-BuOH or Me2C=CH2 4 N HCI ROH RO t-BLI ROH
conc. H2SO4 or BF3 OEt2
Benaylic Ethers
Benzyl Ethers -1 Benzyl ethers are quite stable under both acidic and basic conditions and toward a wide variety of oxidizing and reducing reagents. Hence, they are frequently used in organic syntheses as protecting groups. It should be noted, however, that n-BuLi may deprotonate a benzylic hydrogen, especially in the presence of TMEDA (tetra- methylethylenediamine) or HMPA (hexamethylphosphoramide).
12
2.3.2. par passage à un éther tertiobutylique
2.3.3. en utilisant le chlorure de benzyle
Autre exemple :
62 t' :b+;~Tt? The Concept of Protecting Functional Groups
Formation: Methods for cleavage: a. NaH, THF PdIC, H2, EtOH
ROH ROCH2 Ph ROH + H3CPh b. PhCH2Br or
Ra-Ni, EtOH or
NaO, NH3 (I), EtOH
Catalytic hydrogenolysis offers the mildest method for deprotecting benzyl ethers. Hydrogenolysis of 2'- and 3"-benzyl ethers may be sluggish. Protection of alcohols using (benzy1oxy)methyl chloride produces the corresponding (benzy1oxy)methyl ethers (RO-BOM), which are cleaved inore readily than the corresponding ROBn ethers.I3
ROH RO-CH2-OBn ROH (i-P r)2N Et, CH2C l2 \ , H2, EtOH
BOM group
rhcid-6=a&lyzed Benzylation. Benzyl trichloroacetirnidate, Cl,CC(=NH)OBn, reacts with hydroxyl groups under acid catalysis to give the corresponding benzyl ethers in good yield.I4 The method is particularly useful for the protection of base- sensitive substrates (i.e., alkoxide-sensitive), such as hydroxy estersI5 or hydroxy lac- tones, as exemplified below.'"
NH OTf cat. TfOH
Cl 3 c A 0 ~ P h
benzyl trichloroacetimidate
L J
active benzylating agent
ROH NH2 I
protected alcohol
C13CC(=NH)OBn
L O B n Me0 - cvclohexane
HO hexane, CH2CI2, rt BnO
p-Methoxybenzyl Ethers I RO-PMB / The PMB ether, also refelred to as an MPM ether [(4-methoxyphenyl)methyl], is less stable to acids than a benzyl ether. Its utility as a protecting group stems from the fact that it can be removed oxidatively with DDQ (2,3-dichloro-5,6-dicyano-1,4-benzo- quinone) under conditions that do not affect protecting groups such as acetals, RO-Bn (or RO-BOM), RO-MOM, RO-MEM, RO-THP, RO-TBS, benzoyl, tosyl, or acetate groups, nor do they affect epoxides or ketones.17 Alternatively, RO-PMB ethers can be cleaved with (Nhl,),Ce(NO,),. I S
is to use a third type of hydroxyl-protecting group, a benzyl ether.Benzyl (Bn) protecting groups are put on using strong base (usu-ally sodium hydride) plus benzyl bromide, and are stable to bothacid and base.
The benzyl ether’s Achilles’ heel is the aromatic ring and, after reading the first half of this chap-ter, you should be able to suggest conditions that will take it off again: hydrogenation (hydrogenoly-sis) over a palladium catalyst.
Benzyl ethers can sometimes be removed by acid, if the acid has a nucleophilic conjugate base.HBr, for example, will remove a benzyl ether because Br– is a good enough nucleophile to displaceROH, though only at the reactive, benzylic centre.
HBr in acetic acid (just the solvent) is used to remove the benzyl ether protecting groups in thisexample, which forms part of a synthesis of the alkaloid galanthamine.
We said earlier that simple methyl ethers are inappropriate as protecting groups for OH becausethey are too hard to take off again. That is usually true, but not if the OH is phenolic—ArOH is an
One functional group may be more reactive than another 635
!Note the abbreviation for a benzyl ether, ROCH2Ph, is ROBn. Contrast thiswith benzoyl esters, ROCOPh, which may be abbreviated ROBz.
OTHP
Me
HO OTHP
Me
OPh OH
Me
BnO
Br
Me
BnO Li
Me
BnO
Ph Br
NaHthe benzyl (Bn) protecting group
H3O
THP removed in acid
Bn survives acid
Bn survives base
!It must be a palladium catalyst—platinum would catalysehydrogenation of the aromaticring.
ROPh + ROHPhMe
benzyl ether deprotection: catalytic hydrogenation
H2, Pd/C
ROPh + ROHPhCH2Br
ROPh
H
ROH
Ph
Br
HBr
Br– is a good nucleophile
protonation makes ROH a good leaving group
benzylic centre means fast SN2
benzyl ether deprotection: acid with nucleophilic counterion
ONMe
OH
MeO
NMe
MeOO
OH
HO
Br
NMe
MeOO
OBn
BnO
BrMeO
BnO
Br
COCl
BnO
NHMe
+
galanthamine
two more stepsHBr
AcOH
!Alkaloids appear in Chapter 51.
Protecting group Structure Protects From Protection Deprotection
benzyl ether alcohols (OH almost NaH, BnBr H2, Pd/C, or HBr(OBn) in general) everything
methyl ether phenols bases NaH, MeI, or BBr3, HBr, HI,(ArOMe) (ArOH) (MeO)2SO2 Me3SiI
RO
ROBn
MeO
R
13
2.3.4. en utilisant les éthers silylés mobile, susceptible de réagir avec la base très base qu’est l’ion alcynure (alcynure de Ci-‐dessous, le groupe hydroxyle OH doit être protégé car il possède une hydrogène mobile, susceptible de réagir avec la base très base qu’est l’ion alcynure (alcynure de lithium). Il est très fréquent de protéger le groupe hydrolxyle en préparant un éther silylé :
TBDMS : TertioButylDiMéthylSilane Que ce serait-‐il passer sans protection ?
A la fin de la synthèse, il faut déprotéger la fonction alcool, et régénérer le groupe hydroxyle ; une réaction de substitution nucléophile a alors lieu sur l’atome de silicium de la fonction éther :
Pour information, en conclusion :
One way to make it is to add a Grignard reagent twice to ethyl formate. But, of course, a ketone-containing Grignard is an impossibility as it would self-destruct, so an acetal-protected compoundwas used.
Strongly nucleophilic reagents like Grignard reagents and organolithiums are also strong bases,and may need protecting from acidic protons as well as from electrophilic carbonyl groups. Amongthe most troublesome are the protons of hydroxyl groups. When some American chemists wanted tomake the antiviral agent Brefeldin A, they needed a simple alkynol.
A synthesis could start with the same bromoketone as the one above: reduction gives an alcohol,but alkylation of an alkynyl anion with this compound is not possible, because the anion will justdeprotonate the hydroxyl group.
The answer is to protect the hydroxyl group, and the group chosen here was a silyl ether. Suchethers are made by reacting the alcohol with a trialkylsilyl chloride (here t-butyl dimethyl silylchloride, or TBDMSCl) in the presence of a weak base, usually imidazole, which also acts as anucleophilic catalyst (Chapter 12).
Silicon has a strong affinity for electronegative elements, particularly O, F, and Cl, so trialkyl-silyl ethers are attacked by hydroxide ion, water, or fluoride ion but are more stable to carbonor nitrogen bases or nucleophiles. They are usually removed with aqueous acid or fluoride salts,particularly Bu4N+F– which is soluble in organic solvents. In fact, TBDMS is one member of awhole family of trialkylsilyl protecting groups and their relative stability to nucleophiles of variouskinds is determined by the three alkyl groups carried by silicon. The most labile, trimethylsilyl(TMS), is removed simply on treatment with methanol, while the most stable require hydrofluoricacid.
One functional group may be more reactive than another 633
RO SiMe3
RO SiMe2But
O HO OHOO OO
OHOO OO
Br Br MgBr
O OOH
H cat. Mg, Et2O HCO2Et
H
H2O
OH
Br
OHO
BrLi Li
Br
OHreduce
(e.g. NaBH4)
deprotonation of hydroxyl group by strongly basic reagent
reacts here not here
NHN
(a weak base)imidazole =
Br
OH
Br
OSi
Me
Me
t-Bu
Si
Me
Me
t-Bu
ClLi OTBDMS
the TBDMS protecting group
imidazole
!Although not important to ourdiscussion here, these substitutionreactions are not the simple SN2reactions (Chapter 17) they mightappear to be. The nucleophile adds tosilicon first to form a five-valent anionwhich decomposes with the loss of thealcohol (Chapter 21).
RO
Sit-Bu
Me Me
RO
Sit-Bu
Me Me
H
H2O
ROHRO
Sit-Bu
Me Me F
ROHH3OF
(often Bu4N+F–)
Protecting group Structure Protects From Protection Deprotection
trialkylsilyl alcohols (OH nucleophiles, R3SiCl, base H+, H2O, or F–
(R3Si-, e.g. TBDMS) in general) C or N bases
One way to make it is to add a Grignard reagent twice to ethyl formate. But, of course, a ketone-containing Grignard is an impossibility as it would self-destruct, so an acetal-protected compoundwas used.
Strongly nucleophilic reagents like Grignard reagents and organolithiums are also strong bases,and may need protecting from acidic protons as well as from electrophilic carbonyl groups. Amongthe most troublesome are the protons of hydroxyl groups. When some American chemists wanted tomake the antiviral agent Brefeldin A, they needed a simple alkynol.
A synthesis could start with the same bromoketone as the one above: reduction gives an alcohol,but alkylation of an alkynyl anion with this compound is not possible, because the anion will justdeprotonate the hydroxyl group.
The answer is to protect the hydroxyl group, and the group chosen here was a silyl ether. Suchethers are made by reacting the alcohol with a trialkylsilyl chloride (here t-butyl dimethyl silylchloride, or TBDMSCl) in the presence of a weak base, usually imidazole, which also acts as anucleophilic catalyst (Chapter 12).
Silicon has a strong affinity for electronegative elements, particularly O, F, and Cl, so trialkyl-silyl ethers are attacked by hydroxide ion, water, or fluoride ion but are more stable to carbonor nitrogen bases or nucleophiles. They are usually removed with aqueous acid or fluoride salts,particularly Bu4N+F– which is soluble in organic solvents. In fact, TBDMS is one member of awhole family of trialkylsilyl protecting groups and their relative stability to nucleophiles of variouskinds is determined by the three alkyl groups carried by silicon. The most labile, trimethylsilyl(TMS), is removed simply on treatment with methanol, while the most stable require hydrofluoricacid.
One functional group may be more reactive than another 633
RO SiMe3
RO SiMe2But
O HO OHOO OO
OHOO OO
Br Br MgBr
O OOH
H cat. Mg, Et2O HCO2Et
H
H2O
OH
Br
OHO
BrLi Li
Br
OHreduce
(e.g. NaBH4)
deprotonation of hydroxyl group by strongly basic reagent
reacts here not here
NHN
(a weak base)imidazole =
Br
OH
Br
OSi
Me
Me
t-Bu
Si
Me
Me
t-Bu
ClLi OTBDMS
the TBDMS protecting group
imidazole
!Although not important to ourdiscussion here, these substitutionreactions are not the simple SN2reactions (Chapter 17) they mightappear to be. The nucleophile adds tosilicon first to form a five-valent anionwhich decomposes with the loss of thealcohol (Chapter 21).
RO
Sit-Bu
Me Me
RO
Sit-Bu
Me Me
H
H2O
ROHRO
Sit-Bu
Me Me F
ROHH3OF
(often Bu4N+F–)
Protecting group Structure Protects From Protection Deprotection
trialkylsilyl alcohols (OH nucleophiles, R3SiCl, base H+, H2O, or F–
(R3Si-, e.g. TBDMS) in general) C or N bases
One way to make it is to add a Grignard reagent twice to ethyl formate. But, of course, a ketone-containing Grignard is an impossibility as it would self-destruct, so an acetal-protected compoundwas used.
Strongly nucleophilic reagents like Grignard reagents and organolithiums are also strong bases,and may need protecting from acidic protons as well as from electrophilic carbonyl groups. Amongthe most troublesome are the protons of hydroxyl groups. When some American chemists wanted tomake the antiviral agent Brefeldin A, they needed a simple alkynol.
A synthesis could start with the same bromoketone as the one above: reduction gives an alcohol,but alkylation of an alkynyl anion with this compound is not possible, because the anion will justdeprotonate the hydroxyl group.
The answer is to protect the hydroxyl group, and the group chosen here was a silyl ether. Suchethers are made by reacting the alcohol with a trialkylsilyl chloride (here t-butyl dimethyl silylchloride, or TBDMSCl) in the presence of a weak base, usually imidazole, which also acts as anucleophilic catalyst (Chapter 12).
Silicon has a strong affinity for electronegative elements, particularly O, F, and Cl, so trialkyl-silyl ethers are attacked by hydroxide ion, water, or fluoride ion but are more stable to carbonor nitrogen bases or nucleophiles. They are usually removed with aqueous acid or fluoride salts,particularly Bu4N+F– which is soluble in organic solvents. In fact, TBDMS is one member of awhole family of trialkylsilyl protecting groups and their relative stability to nucleophiles of variouskinds is determined by the three alkyl groups carried by silicon. The most labile, trimethylsilyl(TMS), is removed simply on treatment with methanol, while the most stable require hydrofluoricacid.
One functional group may be more reactive than another 633
RO SiMe3
RO SiMe2But
O HO OHOO OO
OHOO OO
Br Br MgBr
O OOH
H cat. Mg, Et2O HCO2Et
H
H2O
OH
Br
OHO
BrLi Li
Br
OHreduce
(e.g. NaBH4)
deprotonation of hydroxyl group by strongly basic reagent
reacts here not here
NHN
(a weak base)imidazole =
Br
OH
Br
OSi
Me
Me
t-Bu
Si
Me
Me
t-Bu
ClLi OTBDMS
the TBDMS protecting group
imidazole
!Although not important to ourdiscussion here, these substitutionreactions are not the simple SN2reactions (Chapter 17) they mightappear to be. The nucleophile adds tosilicon first to form a five-valent anionwhich decomposes with the loss of thealcohol (Chapter 21).
RO
Sit-Bu
Me Me
RO
Sit-Bu
Me Me
H
H2O
ROHRO
Sit-Bu
Me Me F
ROHH3OF
(often Bu4N+F–)
Protecting group Structure Protects From Protection Deprotection
trialkylsilyl alcohols (OH nucleophiles, R3SiCl, base H+, H2O, or F–
(R3Si-, e.g. TBDMS) in general) C or N bases
One way to make it is to add a Grignard reagent twice to ethyl formate. But, of course, a ketone-containing Grignard is an impossibility as it would self-destruct, so an acetal-protected compoundwas used.
Strongly nucleophilic reagents like Grignard reagents and organolithiums are also strong bases,and may need protecting from acidic protons as well as from electrophilic carbonyl groups. Amongthe most troublesome are the protons of hydroxyl groups. When some American chemists wanted tomake the antiviral agent Brefeldin A, they needed a simple alkynol.
A synthesis could start with the same bromoketone as the one above: reduction gives an alcohol,but alkylation of an alkynyl anion with this compound is not possible, because the anion will justdeprotonate the hydroxyl group.
The answer is to protect the hydroxyl group, and the group chosen here was a silyl ether. Suchethers are made by reacting the alcohol with a trialkylsilyl chloride (here t-butyl dimethyl silylchloride, or TBDMSCl) in the presence of a weak base, usually imidazole, which also acts as anucleophilic catalyst (Chapter 12).
Silicon has a strong affinity for electronegative elements, particularly O, F, and Cl, so trialkyl-silyl ethers are attacked by hydroxide ion, water, or fluoride ion but are more stable to carbonor nitrogen bases or nucleophiles. They are usually removed with aqueous acid or fluoride salts,particularly Bu4N+F– which is soluble in organic solvents. In fact, TBDMS is one member of awhole family of trialkylsilyl protecting groups and their relative stability to nucleophiles of variouskinds is determined by the three alkyl groups carried by silicon. The most labile, trimethylsilyl(TMS), is removed simply on treatment with methanol, while the most stable require hydrofluoricacid.
One functional group may be more reactive than another 633
RO SiMe3
RO SiMe2But
O HO OHOO OO
OHOO OO
Br Br MgBr
O OOH
H cat. Mg, Et2O HCO2Et
H
H2O
OH
Br
OHO
BrLi Li
Br
OHreduce
(e.g. NaBH4)
deprotonation of hydroxyl group by strongly basic reagent
reacts here not here
NHN
(a weak base)imidazole =
Br
OH
Br
OSi
Me
Me
t-Bu
Si
Me
Me
t-Bu
ClLi OTBDMS
the TBDMS protecting group
imidazole
!Although not important to ourdiscussion here, these substitutionreactions are not the simple SN2reactions (Chapter 17) they mightappear to be. The nucleophile adds tosilicon first to form a five-valent anionwhich decomposes with the loss of thealcohol (Chapter 21).
RO
Sit-Bu
Me Me
RO
Sit-Bu
Me Me
H
H2O
ROHRO
Sit-Bu
Me Me F
ROHH3OF
(often Bu4N+F–)
Protecting group Structure Protects From Protection Deprotection
trialkylsilyl alcohols (OH nucleophiles, R3SiCl, base H+, H2O, or F–
(R3Si-, e.g. TBDMS) in general) C or N bases
14
Autres exemples
IV Faut-‐il toujours protéger ? La protection de groupe est-‐elle en accord avec les différents principes de la chimie verte ? Non, car une protection induit deux réactions au moins supplémentaires, avec l’utilisation de solvant, peut être un chauffage,… Les principes de chimie verte stipulent qu’il est préférable d’éviter les recours aux protections de groupes. Mais cela n’est pas toujours possible. Parfois, il est préférable d’utiliser un réactif en très large excès, plutôt que d’avoir recours systématiquement à une protection. Exemple :
One way to make it is to add a Grignard reagent twice to ethyl formate. But, of course, a ketone-containing Grignard is an impossibility as it would self-destruct, so an acetal-protected compoundwas used.
Strongly nucleophilic reagents like Grignard reagents and organolithiums are also strong bases,and may need protecting from acidic protons as well as from electrophilic carbonyl groups. Amongthe most troublesome are the protons of hydroxyl groups. When some American chemists wanted tomake the antiviral agent Brefeldin A, they needed a simple alkynol.
A synthesis could start with the same bromoketone as the one above: reduction gives an alcohol,but alkylation of an alkynyl anion with this compound is not possible, because the anion will justdeprotonate the hydroxyl group.
The answer is to protect the hydroxyl group, and the group chosen here was a silyl ether. Suchethers are made by reacting the alcohol with a trialkylsilyl chloride (here t-butyl dimethyl silylchloride, or TBDMSCl) in the presence of a weak base, usually imidazole, which also acts as anucleophilic catalyst (Chapter 12).
Silicon has a strong affinity for electronegative elements, particularly O, F, and Cl, so trialkyl-silyl ethers are attacked by hydroxide ion, water, or fluoride ion but are more stable to carbonor nitrogen bases or nucleophiles. They are usually removed with aqueous acid or fluoride salts,particularly Bu4N+F– which is soluble in organic solvents. In fact, TBDMS is one member of awhole family of trialkylsilyl protecting groups and their relative stability to nucleophiles of variouskinds is determined by the three alkyl groups carried by silicon. The most labile, trimethylsilyl(TMS), is removed simply on treatment with methanol, while the most stable require hydrofluoricacid.
One functional group may be more reactive than another 633
RO SiMe3
RO SiMe2But
O HO OHOO OO
OHOO OO
Br Br MgBr
O OOH
H cat. Mg, Et2O HCO2Et
H
H2O
OH
Br
OHO
BrLi Li
Br
OHreduce
(e.g. NaBH4)
deprotonation of hydroxyl group by strongly basic reagent
reacts here not here
NHN
(a weak base)imidazole =
Br
OH
Br
OSi
Me
Me
t-Bu
Si
Me
Me
t-Bu
ClLi OTBDMS
the TBDMS protecting group
imidazole
!Although not important to ourdiscussion here, these substitutionreactions are not the simple SN2reactions (Chapter 17) they mightappear to be. The nucleophile adds tosilicon first to form a five-valent anionwhich decomposes with the loss of thealcohol (Chapter 21).
RO
Sit-Bu
Me Me
RO
Sit-Bu
Me Me
H
H2O
ROHRO
Sit-Bu
Me Me F
ROHH3OF
(often Bu4N+F–)
Protecting group Structure Protects From Protection Deprotection
trialkylsilyl alcohols (OH nucleophiles, R3SiCl, base H+, H2O, or F–
(R3Si-, e.g. TBDMS) in general) C or N bases
Why can’t we just use a simple alkyl ether (methyl, say) to protect a hydroxyl group? There is noproblem making the ether, and it will survive most reactions—but there is a problem getting an etheroff again. This is always a consideration in protecting group chemistry—you want a group that is sta-ble to the conditions of whatever reaction you are going to do (in these examples, strong bases andnucleophiles), but can then be removed under mild conditions that do not result in total decomposi-tion of a sensitive molecule. What we need then, is an ether that has an ‘Achilles’ heel’—a feature thatmakes it susceptible to attack by some specific reagent or under specific conditions. One such groupis the tetrahydropyranyl (THP) group. Although it is stable under basic conditions, as an etherwould be, it is an acetal—the presence of the second oxygen atom is its ‘Achilles’ heel’ and makes theTHP protecting group susceptible to hydrolysis under acidic conditions. You could see the lone pairon the second oxygen atom as a ‘safety catch’ that is released only in the presence of acid.
Making the THP acetal has to be done in a slightly unusual way because the usual carbonyl com-pound plus two alcohols is inappropriate. Alcohols are protected by reacting them with an enolether, dihydropyran, under acid catalysis. Notice the oxonium intermediate (formed by a familiarmechanism from Chapter 14)—just as in a normal acetal-forming reaction. In this example the THPgroup is at work preventing a hydroxyl group from interfering in the reduction of an ester.
The THP-protected compound above is an intermediate in a synthesis of the insecticide milbe-mycin as a single enantiomer. It needs to be converted to this alkyne—and now the other hydroxylgroup will need protecting.
This time, though, TBDMS will not do, because the protecting group needs to withstand theacidic conditions needed to remove the THP protecting group! What is more, the protecting groupneeds to be able to survive acid conditions in later steps of the synthesis of the insecticide. The answer
634 24 . Chemoselectivity: selective reactions and protection
R O OR O O
H
R OH
O HO OR OTHP =
the THP protecting group H H2O
!Some chemistry of enol ethers is inChapter 21.
MeO2COH
Me
MeO2CO
Me
O
O
H
OROH
RO O
OTHP
Me
HO
O
dihydropyran
H cat. the THP protecting group
mechanism:
LiAlH4
dihydropyran
!A little further inspection will show you that the THP group here is not just stopping the OH interfering with the LiAlH4 reduction, but is also crucial to thepreservation of the chirality of this compound. The wedged bond shows you that the starting material is a single enantiomer: without a protecting group onone of the hydroxyls, they would be identical and the compound would no longer be chiral. More detailed inspection shows that the THP group alsocomplicates the situation by introducing an extra chiral centre, and hence the potential for two diastereoisomers, which we will ignore.
Protecting group Structure Protects From Protection Deprotection
tetrahydropyranyl alcohols (OH strong bases H+, H2O(THP) in general)
RO O O
dihydro-pyranandacid
Me
HOOTHP
Me
HO
hydroxyl group needs protecting
We have dealt with protecting groups for C=O, OH, and NH that resist nucleophiles, acids, andbase. Sometimes functional groups need protecting against oxidation, and we finish our introduc-tion to protecting groups with an example. During a synthesis of the bacterial product rapamycin, anepoxy alcohol needed converting to a ketone through a sequence that involves selective oxidation ofonly one of two hydroxyl groups. The group to be oxidized is there in the starting material, so it canbe protected straight away. The protecting group (Bn) needs to be acid-stable, because the next stepis to open the epoxide with methanol, revealing the second hydroxyl group. This then needs protect-ing—TBDMS was chosen, so as to be stable to hydrogenolysis, which deprotects the hydroxyl thatwe want to oxidize. Finally, oxidation gives the ketone.
In this chapter we have talked about most of the steps in this sequence, except the epoxide-open-ing reaction (for which read Chapters 17 and 18) and the oxidation step. Which reagent would achemist choose to oxidize the alcohol to the ketone, and why? We shall now move on to look at oxi-dizing agents in detail.
Oxidizing agentsWe dealt in detail earlier in the chapter with reducing agents and their characteristic chemoselectivi-ties. Oxidizing agents are equally important, and in the chapter on electrophilic addition to alkeneswe told you about peracids as oxidizing agents for C=C double bonds—they give epoxides. But
Oxidizing agents 637
Protecting group Structure Protects From Protection Deprotection
benzyl ether alcohols (OH almost NaH, BnBr H2, Pd/C, or HBr(OBn) in general) everything
methyl ether phenols bases NaH, MeI, or BBr3, HBr, HI,(ArOMe) (ArOH) (MeO)2SO2 Me3SiI
benzyl amine amines strong bases BnBr, K2CO3 H2, Pd(NBn)
RO
ROBn
MeO
R
RHN
RNHBn
Bergamotene
An acidic proton posed a potential problem duringE.J. Corey’s synthesis of bergamotene (acomponent of the fragrance of Earl Grey tea). Youmet the Wittig reaction in Chapter 14, andphosphonium ylids are another type of basic,
nucleophilic reagent that –OH groups often needprotecting against. But, in this synthesis, asuccessful Wittig reaction was carried out even inthe presence of a carboxylic acid, again by using anexcess of the phosphonium ylid. We talk about
carboxylic acid protection in the next chapter. Infact the carboxylate anion is itself a kind ofprotecting group as it discourages the rather basicWittig reagent from removing a proton to form anenolate.
OH
OO
ROH
O
RPh3P CH2
O
OO
RPh3P CH2
O
O
Rfirst
equivalentsecond
equivalent
H
work-up
OH
O
OBn
O
OBn
OH
OMe
OBn
OSit-BuMe2
OMe
OH
OSit-BuMe2
OMe
O
OSit-BuMe2
OMe
NaH, BnBr MeOH, H+t-BuMe2SiX,base
H2, Pd, C oxidize
!In Chapter 37 you will find out thatperacids also react with ketones,but that need not concern ushere.
We have dealt with protecting groups for C=O, OH, and NH that resist nucleophiles, acids, andbase. Sometimes functional groups need protecting against oxidation, and we finish our introduc-tion to protecting groups with an example. During a synthesis of the bacterial product rapamycin, anepoxy alcohol needed converting to a ketone through a sequence that involves selective oxidation ofonly one of two hydroxyl groups. The group to be oxidized is there in the starting material, so it canbe protected straight away. The protecting group (Bn) needs to be acid-stable, because the next stepis to open the epoxide with methanol, revealing the second hydroxyl group. This then needs protect-ing—TBDMS was chosen, so as to be stable to hydrogenolysis, which deprotects the hydroxyl thatwe want to oxidize. Finally, oxidation gives the ketone.
In this chapter we have talked about most of the steps in this sequence, except the epoxide-open-ing reaction (for which read Chapters 17 and 18) and the oxidation step. Which reagent would achemist choose to oxidize the alcohol to the ketone, and why? We shall now move on to look at oxi-dizing agents in detail.
Oxidizing agentsWe dealt in detail earlier in the chapter with reducing agents and their characteristic chemoselectivi-ties. Oxidizing agents are equally important, and in the chapter on electrophilic addition to alkeneswe told you about peracids as oxidizing agents for C=C double bonds—they give epoxides. But
Oxidizing agents 637
Protecting group Structure Protects From Protection Deprotection
benzyl ether alcohols (OH almost NaH, BnBr H2, Pd/C, or HBr(OBn) in general) everything
methyl ether phenols bases NaH, MeI, or BBr3, HBr, HI,(ArOMe) (ArOH) (MeO)2SO2 Me3SiI
benzyl amine amines strong bases BnBr, K2CO3 H2, Pd(NBn)
RO
ROBn
MeO
R
RHN
RNHBn
Bergamotene
An acidic proton posed a potential problem duringE.J. Corey’s synthesis of bergamotene (acomponent of the fragrance of Earl Grey tea). Youmet the Wittig reaction in Chapter 14, andphosphonium ylids are another type of basic,
nucleophilic reagent that –OH groups often needprotecting against. But, in this synthesis, asuccessful Wittig reaction was carried out even inthe presence of a carboxylic acid, again by using anexcess of the phosphonium ylid. We talk about
carboxylic acid protection in the next chapter. Infact the carboxylate anion is itself a kind ofprotecting group as it discourages the rather basicWittig reagent from removing a proton to form anenolate.
OH
OO
ROH
O
RPh3P CH2
O
OO
RPh3P CH2
O
O
Rfirst
equivalentsecond
equivalent
H
work-up
OH
O
OBn
O
OBn
OH
OMe
OBn
OSit-BuMe2
OMe
OH
OSit-BuMe2
OMe
O
OSit-BuMe2
OMe
NaH, BnBr MeOH, H+t-BuMe2SiX,base
H2, Pd, C oxidize
!In Chapter 37 you will find out thatperacids also react with ketones,but that need not concern ushere.
15
Principes concernés parmi les douze :
LES 12 PRINCIPES DE LA CHIMIE VERTE Paul T. Anastas et John C. Warner ont publié, à la fin des années quatre-vingt-dix, douze principes nécessaires à l'établissement d'une chimie durable.
1. Prévention : limiter la pollution à la source plutôt que devoir éliminer les déchets ;
2. Économie d'atomes : optimiser l'incorporation des réactifs dans le produit final ;
3. Conception de synthèses chimiques moins dangereuses qui utilisent et conduisent à des produits peu ou pas toxiques ;
4. Conception de produits chimiques plus sûrs : efficaces et moins toxiques ;
5. Réduction de l'utilisation de solvants et d'auxiliaires ; 6. Réduction de la dépense énergétique ; 7. Utilisation de matières premières renouvelables au lieu de matières
fossiles ; 8. Réduction des produits dérivés qui peuvent notamment générer des
déchets ; 9. Utilisation de la catalyse ; 10. Conception des substances en intégrant leur mode de dégradation
finale ; 11. Mise au point de méthodes d'analyse en temps réel pour prévenir la
pollution ; 12. Développement d'une chimie sécuritaire pour prévenir les accidents,
les explosions, les incendies et les rejets.
even better leaving group than ROH, so HBr will take off methyl groups from aryl methyl ethers too.You will see an example in Chapter 25.
Protecting groups may be useful, but they are also wasteful—both of time, because there are twoextra steps to do (putting the group on and taking it off), and of material, because these steps maynot go in 100% yield. Here’s one way to avoid using them. During the development of the best-sell-ing anti-asthma drug salbutamol, the triol boxed in green was needed. With large quantities of salbu-tamol already available, it seemed most straightforward to make the triol by addingphenylmagnesium bromide to an ester available from salbutamol. Unfortunately, the ester also con-tains three acidic protons, making it look as though the hydroxyl and amine groups all need protect-ing. But, in fact, it was possible to do the reaction just by adding a large excess of Grignard reagent:enough to remove the acidic protons and to add to the ester.
This strategy is easy to try, and, providing the Grignard reagent isn’t valuable (you can buyPhMgBr in bottles), is much more economical than putting on protecting groups and taking themoff again. But it doesn’t always work—there is no way of telling whether it will until you try the reac-tion in the lab. In this closely related reaction, for example, the same chemists found that they need-ed to protect both the phenolic hydroxyl group (but not the other, normal alcohol OH!) as a benzylether and the amine NH as a benzyl amine. Both protecting groups come off in one hydrogenationstep.
Benzyl groups are one way of protecting secondary amines against strong bases that might depro-tonate them. But it is the nucleophilicity of amines that usually poses problems of chemoselectivity,rather than the acidity of their NH groups, and we come back to ways of protecting them from elec-trophiles when we deal with the synthesis of peptides in Chapter 25.
636 24 . Chemoselectivity: selective reactions and protection
!Alternatives to HBr include BBr3,usually the favoured reagent, HI,and Me3SiI. You met the reactionof phenyl ethers with BBr3 inChapter 17. + MeBrArOHArOMe
HBr
deprotection of aryl methyl ethers
OMe
H
OH
Me
Br
HO
HO
OH
Nt-Bu
H
MeO2C
HO
OH
Nt-Bu
H
HO
HO
OH
Nt-Bu
HPh Ph
salbutamol three acidic protons
PhMgBr
(at least 5 equivs)
triol
MeO2C
BnO
OH
N
Ph
BnO
OH
N
Ph
HO
HO
OHHN
HO
(excess)
H2,
Pd/C
MeMgBr
!This is the last appearance of the tableof protecting groups in this chapter butit is extended in Chapter 25.
Protecting group Structure Protects From Protection Deprotection
acetal ketones, nucleophiles, water, H+ cat.(dioxolane) aldehydes bases
trialkylsilyl alcohols (OH nucleophiles, R3SiCl, base H+, H2O, or F–
(R3Si-, e.g. TBDMS) in general) C or N bases
tetrahydropyranyl alcohols (OH strong bases H+, H2O(THP) in general)
R R
OO HOOH
RO O O
dihydro-pyranandacid
3 protons acides
combien faut-il d’équivalents d’organomagnésien ?
