Silyl Ethers - Thieme Chemistry
Silyl Ethers - Thieme Chemistry
Silyl Ethers - Thieme Chemistry
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4.4.17 Product Subclass 17:<br />
<strong>Silyl</strong> <strong>Ethers</strong><br />
J. D. White and R. G. Carter<br />
General Introduction<br />
FOR PERSONAL USE ONLY<br />
A useful feature of silyl ethers is that they greatly increase the volatility of an otherwise<br />
nonvolatile polyol. A highly polar and intractable oligosaccharide, for example, can be<br />
rendered amenable to gas chromatography and mass spectrometry through exhaustive<br />
silylation of its free hydroxy groups. However, the most frequent use made of silyl ethers<br />
is for the protection of alcohols. [1,2] Virtually any primary, secondary, or tertiary alcohol<br />
can be converted into a silyl ether, and there is usually the option of differential protection<br />
of polyhydroxylic structures with an appropriate choice of silylating agent. [3] By far<br />
the most general method for preparation of a silyl ether is through the reaction of an alcohol<br />
with a silylating agent that bears a leaving group. Chlorosilanes and silyl triflates<br />
are the most common reagents for this purpose, and are typically used in the presence<br />
of a base. The nature of this base can significantly affect the reactivity of the silylating<br />
agent.<br />
The ability to modulate the reactivity of the silylating agent through variation of the<br />
substituents on silicon contributes much versatility to the synthesis of silyl ethers. It is<br />
also an important factor in the selective cleavage of silyl ethers (deprotection). Both steric<br />
and electronic properties of the substituents at silicon play a role in the formation of silyl<br />
ethers and are especially important when considering the stability of a silyl ether toward<br />
acids and bases. For some of the most commonly used silyl ethers, the stability toward<br />
acid increases in the order trimethylsilyl (TMS, 1) < triethylsilyl (TES, 64) < tert-butyldimethylsilyl<br />
(TBDMS, 2 ” 10 4 ) < triisopropylsilyl (TIPS, 7 ” 10 5 )
ly common with tert-butyldimethylsilyl ethers, [9] but less so with triisopropylsilyl and tertbutyldiphenylsilyl<br />
ethers. <strong>Silyl</strong> migration of this type is most frequently seen where oxygens<br />
bear a 1,2-relationship [10] or a 1,3-relationship, [11] although more distant migrations<br />
are known. This aspect of silyl ether chemistry has sometimes presented problems in<br />
complex syntheses where a specific hydroxy protection is desired. It can pose severe difficulties<br />
for researchers in the fields of carbohydrate [12] and ribooligonucleotide [13] synthesis<br />
where unwanted silyl migrations often occur quite readily.<br />
<strong>Silyl</strong> migration between carbon and oxygen has long been recognized as an important<br />
feature of silicon chemistry; in fact, the rearrangement can be used as a preparative<br />
method for silyl ethers. [14] The transfer of a silyl group from carbon to oxygen was first described<br />
in the context of a [1,2]shift by Brook, [15] for whom the rearrangement is named. It<br />
was subsequently found that migration can occur between nonadjacent atoms, leading to<br />
[1,n]-Brook rearrangements where n £5. [16] It has been shown that silicon retains its configuration<br />
in the course of a Brook rearrangement. [17] The rearrangement requires the<br />
presence of a strong base and is synthetically most useful when the carbanion resulting<br />
from silyl migration is stabilized. [18]<br />
The reverse migration of silyl groups from oxygen to carbon (retro-Brook rearrangement)<br />
was discovered by West, initially as a [1,3]shift [19] and later as a [1,2]migration. [20]<br />
Longer range retro-Brook rearrangements have also been noted. [21] These reactions take<br />
place when silyl ethers are exposed to a strong base, such as an alkyllithium, which may<br />
be used to effect halogen±metal or metal±metal exchange. <strong>Silyl</strong> migration to the resultant<br />
carbanion is driven by the formation of a more stable alkoxide species.<br />
4.4.17.1 Trimethylsilyl <strong>Ethers</strong><br />
As the least stable of the family of silyl ethers, trimethylsilyl (TMS) ethers have found only<br />
limited utility as protecting groups in complex synthesis. Their sensitivity toward mild<br />
acids (e.g., acetic acid) and bases (potassium carbonate in methanol) makes their survival<br />
through multistep operations in a synthetic sequence problematic. Even chromatography<br />
on silica gel can suffice to cleave a trimethylsilyl ether. The most frequent use made of<br />
trimethylsilyl ethers is to mask polar functional groups, primarily hydroxy and carboxy<br />
groups, for the purpose of increasing the volatility of an otherwise nonvolatile compound.<br />
Since trimethylsilyl ethers are thermally quite stable, the resultant (poly)silyl<br />
ether can be subjected to gas chromatography and mass spectrometry without fear of decomposition.<br />
This technique has been widely applied in the carbohydrate area where exhaustive<br />
silylation, for example with N-(trimethylsilyl)acetamide, leads to a persilylated<br />
sugar. [22]<br />
Formation<br />
FOR PERSONAL USE ONLY<br />
372 Science of Synthesis 4.4 Silicon Compounds<br />
4.4.17.1.1 Method 1:<br />
<strong>Silyl</strong>ation ofAlcohols with Chlorotrimethylsilane<br />
A variety of silylating agents is available for the preparation of trimethylsilyl ethers, but<br />
chlorotrimethylsilane (TMSCl) is perhaps the most frequently employed. It is used in the<br />
presence of a base, typically imidazole or triethylamine, which removes hydrogen chloride<br />
formed during the silylation. There is very little difference in the rate of silylation<br />
of primary, secondary, and tertiary alcohols with this reagent, and selectivity in protection<br />
of alcohols is not usually possible. A typical silylation with chlorotrimethylsilane is<br />
that of alcohol 1 to give silyl ether 2 (Scheme 1); it is noteworthy that the terminal alkyne<br />
of 1 does not undergo silylation under these conditions. [23]<br />
White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg <strong>Thieme</strong> Verlag KG
Scheme 1 <strong>Silyl</strong>ation with Chlorotrimethylsilane [23]<br />
H OH<br />
1<br />
OPMB<br />
TMSCl, imidazole<br />
CH2Cl2, rt, 10 h<br />
95%<br />
H OTMS<br />
2<br />
OPMB<br />
(4S,5R)-6-(4-Methoxybenzyloxy)-5-methyl-4-(trimethylsiloxy)hex-1-yne (2): [23]<br />
TMSCl (747 ìL, 5.92 mmol) followed by imidazole (619 mg, 9.10 mmol) were added to a<br />
stirred soln of alcohol 1 (1.129 g, 4.55 mmol) in CH 2Cl 2 (50 mL) at rt under N 2. A white precipitate<br />
formed immediately. The mixture was stirred for 10 h and was then diluted with<br />
EtOAc (100 mL). The organic phase, after washing with H 2O (15 mL) and sat. aq NaCl<br />
(15 mL), was dried (Na 2SO 4), filtered, and concentrated. Column chromatography (silica<br />
gel, hexanes/EtOAc 7:1) of the residue gave 2 as a clear, colorless oil; yield: 1.384 g (95%).<br />
4.4.17.1.2 Method 2:<br />
<strong>Silyl</strong>ation ofAlcohols with Trimethylsilyl Trifluoromethanesulfonate<br />
Trimethylsilyl trifluoromethanesulfonate (trimethylsilyl triflate, TMSOTf), a powerful silylating<br />
agent, [24] has gained popularity among synthetic chemists since it became readily<br />
available from commercial sources. Despite the highly electrophilic character of this reagent,<br />
it is remarkably tolerant of other functionalities providing it is used in the presence<br />
of a base such as a tertiary amine. All alcohols, regardless of their steric environment,<br />
are usually silylated with this reagent, an example being conversion of the ciguatoxin<br />
precursor 3 into its trimethylsilyl ether 4 (Scheme 2). [25]<br />
Scheme 2 <strong>Silyl</strong>ation with Trimethylsilyl Trifluoromethanesulfonate [25]<br />
I<br />
HO<br />
H H<br />
O<br />
BnO<br />
O<br />
H H<br />
3<br />
FOR PERSONAL USE ONLY<br />
4.4.17 <strong>Silyl</strong> <strong>Ethers</strong> 373<br />
OTBDMS<br />
OTBDPS<br />
TMSOTf, Et3N<br />
CH2Cl2, −10<br />
98%<br />
oC I<br />
TMSO<br />
H H<br />
O<br />
BnO<br />
O<br />
H H<br />
4<br />
OTBDMS<br />
OTBDPS<br />
(1R,3S,4R,5S,6S,8R,9S)-5-Benzyloxy-9-(tert-butyldimethylsiloxy)-8-[2-(tert-butyldiphenylsiloxy)ethyl]-3-(2-iodoethyl)-4-(trimethylsiloxy)-2,7-dioxabicyclo[4.4.0]decane<br />
(4): [25]<br />
To a soln of alcohol 3 (68.4 mg, 82.3 ìmol) and Et 3N (45.9 ìL, 329 ìmol) in CH 2Cl 2 was<br />
added dropwise TMSOTf (31.8 ìL, 165 ìmol) at ±108C, and the mixture was stirred at that<br />
temperature for 10 min. The reaction was quenched with sat. aq NaHCO 3, and the aqueous<br />
layer was extracted repeatedly with Et 2O. The combined organic layers were washed<br />
with brine, dried (MgSO 4), filtered, and concentrated in vacuo. The residue was purified<br />
by column chromatography (silica gel, hexane/EtOAc 15:1) to afford 4 as a pale yellow<br />
oil; yield: 72.8 mg (98%).<br />
4.4.17.1.3 Method 3:<br />
<strong>Silyl</strong>ation ofAlcohols with Trimethylsilyl Cyanide<br />
CAUTION: All silyl cyanides should be treated as highly toxic in their own right, and are capable<br />
of generating hydrogen cyanide if exposed to water or moisture. Many silyl cyanide derivatives<br />
are also volatile. All reactions involving the preparation or use of these compounds should be carried<br />
out by appropriately trained personnel in a well-ventilated fume hood and in full compliance<br />
with all local safety regulations regarding the use of cyanides.<br />
for references see p 410<br />
White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg <strong>Thieme</strong> Verlag KG
Trimethylsilyl cyanide (TMSCN) is a reagent used for silylation where the presence of a<br />
base must be avoided. [26] Since the byproduct, hydrogen cyanide, is volatile and not sufficiently<br />
acidic to be deleterious, silylation can be carried out with the neat reagent or in a<br />
neutral solution. The reagent rapidly silylates alcohols, phenols and carboxylic acids, but<br />
reacts only slowly with amines and thiols. Amides are not silylated with this reagent. An<br />
example illustrating the application of this reagent is the conversion of the sensitive<br />
calicheamicinone precursor 5 into its trimethylsilyl ether 7 via the tris(silyl ether) 6<br />
(Scheme 3). [27] It is noteworthy that only the primary trimethylsilyl ether of intermediate<br />
6 is cleaved during workup in the presence of aqueous acetic acid.<br />
Scheme 3 <strong>Silyl</strong>ation with Trimethylsilyl Cyanide [27]<br />
TESO<br />
NHCO2Me<br />
OH<br />
FOR PERSONAL USE ONLY<br />
374 Science of Synthesis 4.4 Silicon Compounds<br />
OBoc OBoc<br />
Me 3SiCN<br />
TESO<br />
HO TMSO<br />
5 6<br />
AcOH, H2O, THF<br />
99%<br />
NHCO2Me<br />
OTMS<br />
TESO<br />
HO<br />
OBoc<br />
7<br />
NHCO2Me<br />
OTMS<br />
Methyl 11-(tert-Butoxycarbonyloxy)-13-(2-hydroxyethylidene)-1-(triethylsiloxy)-8á-<br />
(trimethylsiloxy)bicyclo[7.3.1]trideca-4,9,11-triene-2,6-diyn-10-ylcarbamate (7): [27]<br />
A soln of 5 (465 mg, 0.85 mmol) in TMSCN (1 mL) was stirred for 30 min and the volatiles<br />
were evaporated in vacuo. The residue was dissolved in a mixture of THF (50 mL), H 2O<br />
(10 mL), and glacial AcOH (1 mL). The mixture was stirred for 30 min (with close monitoring<br />
by TLC, Et 2O/petroleum ether 1:1), diluted with Et 2O (150 mL), washed with sat. aq<br />
NaHCO 3 (2 ” 50 mL), dried (MgSO 4), filtered, and evaporated in vacuo to give 7 as a pale<br />
yellow, solid foam; yield: 518 mg (99%).<br />
4.4.17.1.4 Method 4:<br />
<strong>Silyl</strong>ation ofAlcohols with N,O-Bis(trimethylsilyl)acetamide<br />
N,O-Bis(trimethylsilyl)acetamide (BSA) is a relatively unselective reagent that can convert<br />
hindered alcohols into their trimethylsilyl ethers when used in dimethylformamide at elevated<br />
temperature (80±1008C). [28] The byproduct acetamide must be removed, often requiring<br />
chromatography for purification of the silyl ether. The related reagent N,O-bis(trimethylsilyl)trifluoroacetamide,<br />
[29] although used less frequently, has the advantage that<br />
the byproduct, trifluoroacetamide, is removed more easily since it is quite volatile. An application<br />
of N,O-bis(trimethylsilyl)acetamide is seen in the conversion of the alcohol 8<br />
into its trimethylsilyl ether 9 (Scheme 4), an intermediate in a synthetic route to azinomycin.<br />
[30]<br />
White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg <strong>Thieme</strong> Verlag KG
Scheme 4 <strong>Silyl</strong>ation with N,O-Bis(trimethylsilyl)acetamide [30]<br />
AcHN<br />
AcO<br />
CO2Me<br />
Br<br />
HO NCbz<br />
8<br />
BSA, THF, 90 oC, 1 h<br />
92%<br />
AcHN<br />
AcO<br />
CO2Me<br />
Br<br />
TMSO NCbz<br />
Methyl (2E,4S,5R)-4-Acetoxy-2-(acetylamino)-5-[(2S)-1-(benzyloxycarbonyl)aziridin-2-yl]-3bromo-5-(trimethylsiloxy)pent-2-enoate<br />
(9): [30]<br />
A soln of 8 (52 mg, 0.104 mmol) in THF (0.1 mL) was treated with BSA (15.2 ìL,<br />
0.062 mmol, 1.2 equiv), and the mixture was warmed at 908C for 1 h. The reaction was<br />
cooled to 258C, diluted with EtOAc (25 mL), washed with sat. NaCl soln (2 ” 2 mL), and<br />
the organic layer was dried (MgSO 4) and concentrated in vacuo. The residue was purified<br />
by Sephadex LH-20 chromatography to afford 9; yield: 54.5 mg (92%).<br />
Cleavage<br />
4.4.17.1.5 Method 5:<br />
Cleavage ofTrimethylsilyl <strong>Ethers</strong> with Acidic Reagents<br />
Trimethylsilyl ethers are cleaved with exceptional ease under acidic conditions. Thus, it is<br />
quite feasible to unmask an alcohol protected as its trimethylsilyl ether without affecting<br />
other protected hydroxy functions; this includes alcohols protected in the form of virtually<br />
any other silyl ether. One acidic reagent that can be used to selectively cleave a trimethylsilyl<br />
ether is pyridinium 4-toluenesulfonate in methanol, as seen in the transformation<br />
of the sarcodictycine intermediate 10 to the alcohol 11 (Scheme 5). [31] Neither the triisopropylsilyl<br />
ether nor the 4-methoxybenzyl ether of 10 is removed under these conditions.<br />
Scheme 5 Selective Cleavage of a Trimethylsilyl Ether [31]<br />
PMBO<br />
H<br />
H<br />
10<br />
O<br />
OTIPS<br />
OTMS<br />
PPTS, MeOH<br />
rt, 30 min<br />
94%<br />
9<br />
PMBO<br />
H<br />
H<br />
11<br />
OH<br />
O<br />
OTIPS<br />
Dilute hydrochloric acid can also be used to cleave trimethylsilyl ethers, although other<br />
silyl ethers such as triethylsilyl and tert-butyldimethylsilyl are vulnerable under these<br />
conditions. An example illustrating the facile cleavage of a trimethylsilyl ether in the<br />
presence of an epoxide is the deprotection of 12 to give epoxy alcohol 13 (Scheme 6). [32]<br />
Scheme 6 Cleavage of a Trimethylsilyl Ether with Hydrochloric Acid [32]<br />
OH<br />
O<br />
O<br />
H<br />
H<br />
H<br />
OTMS<br />
( +<br />
−)-12<br />
O<br />
FOR PERSONAL USE ONLY<br />
4.4.17 <strong>Silyl</strong> <strong>Ethers</strong> 375<br />
SiMe2Ph<br />
HCl, MeOH, CH2Cl2 0 oC, 30 min<br />
90%<br />
OH<br />
O<br />
O<br />
H<br />
H<br />
OH<br />
H<br />
( +<br />
−)-13<br />
O<br />
SiMe2Ph<br />
for references see p 410<br />
White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg <strong>Thieme</strong> Verlag KG
(1R,7S,8S,10R,14R)-7-Hydroxy-14-isopropyl-8-(4-methoxybenzyloxy)-7,11-dimethyl-3-<br />
(triisopropylsiloxymethyl)bicyclo[8.4.0]tetradeca-2,11-dien-5-yn-4-one (11): [31]<br />
To a soln of 10 (3.2 mg, 4.7 ìmol) in MeOH (1 mL) was added, at 258C, PPTS (1.18 mg,<br />
4.7 ìmol), and the mixture was allowed to stir at rt for 30 min. The reaction was quenched<br />
by the addition of sat. NaHCO 3 soln (1 mL), then extracted with Et 2O (2 ” 10 mL). The combined<br />
organic extracts were dried (Na 2SO 4) and concentrated. The crude product was purified<br />
by flash chromatography (silica gel, EtOAc/hexane 15:85) to provide alcohol 11 as a<br />
colorless oil; yield: 2.7 mg (94%).<br />
rac-(3R,4aS,5R,6S,6aS,12aS,12bR)-3-[Dimethyl(phenyl)silyl]-4a,5-epoxy-6,8-dihydroxy-3methyl-1,2,3,4,4a,5,6,6a,12a,12b-decahydrobenzo[a]anthracene-7,12-dione<br />
(13): [32]<br />
One drop of 1 M HCl was added to a soln of 12 (200 mg, 0.375 mmol) in MeOH (4 mL) and<br />
CH 2Cl 2 (2 mL) at 08C. The mixture was stirred for ca. 0.5 h at 08C and then extracted with<br />
CH 2Cl 2 (50 mL). The organic phase was washed with ice-cold H 2O (2 ” 20 mL), dried<br />
(Na 2SO 4), and the solvent was removed under reduced pressure to afford epoxy alcohol<br />
13 as an unstable, yellow oil containing some (5%) aromatization product; yield: 156 mg<br />
(90%).<br />
4.4.17.1.6 Method 6:<br />
Cleavage ofTrimethylsilyl <strong>Ethers</strong> under Basic Conditions<br />
One of the mildest methods for cleaving a trimethylsilyl ether is through its exposure to<br />
potassium carbonate in methanol, conditions which will not effect cleavage of any other<br />
silyl ether. The selective deprotection of the ciguatoxin precursor 14 bearing three different<br />
silyl ethers, as well as a benzyl ether and an epoxide, exemplifies an application of<br />
this method (Scheme 7). [33]<br />
Scheme 7 Selective Cleavage of a Trimethylsilyl Ether with Base [33]<br />
O<br />
O<br />
TMSO<br />
O<br />
FOR PERSONAL USE ONLY<br />
376 Science of Synthesis 4.4 Silicon Compounds<br />
H H<br />
O<br />
O OTBDPS<br />
H H<br />
BnO<br />
14<br />
OTBDMS<br />
O<br />
O<br />
O<br />
K2CO3, MeOH<br />
0 oC, 1.5 h<br />
96%<br />
H H<br />
O<br />
HO O OTBDPS<br />
H H<br />
BnO<br />
15<br />
OTBDMS<br />
The most widely used method for cleaving silyl ethers is through the use of tetrabutylammonium<br />
fluoride in tetrahydrofuran. This reagent can be used for cleaving trimethylsilyl<br />
ethers, but is not selective with respect to silyl ethers in general. Tetrabutylammonium<br />
fluoride is a sufficiently basic reagent to cause elimination and other side reactions with<br />
base-sensitive compounds, and it will sometimes promote migration of a silyl group to a<br />
neighboring free hydroxy group; however, esters are not usually cleaved with this reagent,<br />
as deprotection of the benzoate 16 reveals (Scheme 8). [34]<br />
White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg <strong>Thieme</strong> Verlag KG
Scheme 8 Cleavage of a Trimethylsilyl Ether with Tetrabutylammonium Fluoride [34]<br />
O<br />
H<br />
O<br />
O<br />
O<br />
H<br />
Bn<br />
TBAF, THF, 0 oC 98%<br />
OTMS OBz<br />
O<br />
OH<br />
16 17<br />
H<br />
O<br />
O<br />
O<br />
H<br />
(1R,3S,4R,5R,6S,8R,9S)-5-Benzyloxy-9-(tert-butyldimethylsiloxy)-8-[2-(tert-butyldiphenylsiloxy)ethyl]-3-{(2Z,4S,5R)-6-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-4,5-epoxyhex-2-enyl}-2,7dioxabicyclo[4.4.0]decan-4-ol<br />
(15): [33]<br />
To a soln of 14 (5.2 mg, 5.50 ìmol) in MeOH (1 mL) was added K 2CO 3 (an excess amount) at<br />
08C, and the mixture was stirred at the same temperature for 1.5 h. The mixture was diluted<br />
with Et 2O, and H 2O was added. The aqueous layer was extracted repeatedly with<br />
EtOAc. The combined organic layers were washed with brine, dried (MgSO 4), filtered,<br />
and concentrated in vacuo. The residue was purified by column chromatography (silica<br />
gel, hexane/EtOAc 3:1) to afford 15 as a colorless oil; yield: 4.6 mg (96%).<br />
[2S-(2á,3aâ,3bâ,6aâ,9aá,9bá,10á,11aâ)]-5-(Benzoyloxymethyl)-2-benzyl-2,9b-epoxy-6ahydroxy-11a-isopropenyl-8,10-dimethyl-3a,3b,6,6a,9a,10,11,11a-octahydro-7H-azuleno[5,4-e]-1,3-benzodioxol-7-one<br />
(17): [34]<br />
To a stirred soln of silyl ether 16 (8 mg, 12.4 ìmol) in THF (1 mL) at 08C was added 1.0 M<br />
TBAF in THF (24 ìL, 24.8 ìmol). After being stirred at 08C for 10 min, the mixture was<br />
poured into sat. aq NH 4Cl (5 mL) and extracted with EtOAc (3 ” 2 mL). The combined organic<br />
extracts were dried (MgSO 4), filtered, and concentrated in vacuo. Purification by flash<br />
chromatography (EtOAc/hexanes 2:8) gave alcohol 17; yield: 6.9 mg (98%).<br />
4.4.17.2 Triethylsilyl <strong>Ethers</strong><br />
Triethylsilyl (TES) ethers are more stable and more resistant to acidic cleavage than trimethylsilyl<br />
ethers. They are often used where exhaustive silylation of a polyol is desired,<br />
but where a per(trimethylsilyl ether) is too labile for purification. The volatility of a triethylsilyl<br />
ether is only slightly less than that of a trimethylsilyl ether; however, the increased<br />
size of the substituents at silicon in a triethylsilyl ether can make this silylation of a tertiary<br />
alcohol quite sluggish, especially with chlorotriethylsilane.<br />
Formation<br />
FOR PERSONAL USE ONLY<br />
4.4.17 <strong>Silyl</strong> <strong>Ethers</strong> 377<br />
4.4.17.2.1 Method 1:<br />
<strong>Silyl</strong>ation ofAlcohols with Chlorotriethylsilane<br />
Triethylsilyl ethers are most frequently prepared using chlorotriethylsilane (TESCl) [35] in<br />
the presence of a base such as imidazole, pyridine or 4-(dimethylamino)pyridine. [36] A typical<br />
silylation with this reagent is that of alcohol 18 carried out in dimethylformamide at<br />
room temperature to give triethylsilyl ether 19 (Scheme 9). [37]<br />
OBz<br />
Bn<br />
for references see p 410<br />
White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg <strong>Thieme</strong> Verlag KG
Scheme 9 <strong>Silyl</strong>ation with Chlorotriethylsilane in the Presence of Imidazole [37]<br />
OH O<br />
PMBO<br />
OMe<br />
N<br />
Me<br />
18<br />
TESCl, imidazole<br />
DMF, rt, 15 h<br />
70%<br />
TESO<br />
O<br />
R R OMe<br />
PMBO S N<br />
Me<br />
(3S)-19<br />
+<br />
89:11<br />
TESO<br />
R R OMe<br />
PMBO R N<br />
Me<br />
(3R)-19<br />
(2R,3S,4R)-N-Methoxy-5-(4-methoxybenzyloxy)-N,2,4-trimethyl-3-(triethylsiloxy)pentanamide<br />
(19): [37]<br />
To a soln of a mixture of alcohol stereoisomers 18 (1.02 g, 3.14 mmol) in DMF (15 mL) were<br />
added imidazole (488 mg, 7.16 mmol) and TESCl (0.9 mL, 5.36 mmol) at rt. After being<br />
stirred for 15 h, the mixture was quenched with H 2O. The organic layer was separated,<br />
washed with 0.5 M aq NaHSO 4, sat. aq NaHCO 3 and brine, dried (Na 2SO 4), and concentrated<br />
to give a residue which was purified by flash chromatography (silica gel, EtOAc/hexane<br />
1:9) to give (3S)-19 as a colorless oil [yield: 855 mg (62%)]along with the 3R-diastereomer<br />
[yield: 106 mg (8%)].<br />
4.4.17.2.1.1 Variation 1:<br />
With Chlorotriethylsilane in Pyridine<br />
Chlorotriethylsilane is more reactive when used with pyridine as the solvent. For example,<br />
a relatively difficult silylation of the hindered alcohol 20 to give triethylsilyl ether 21,<br />
an intermediate in a zaragozic acid synthesis, was carried out with chlorotriethylsilane in<br />
pyridine at room temperature (Scheme 10). [38] The tertiary alcohol in 20 was unaffected<br />
under these conditions.<br />
Scheme 10 <strong>Silyl</strong>ation with Chlorotriethylsilane in Pyridine [38]<br />
OHC<br />
HO<br />
O<br />
O<br />
Bu t O 2C<br />
O<br />
CO 2Bu t<br />
CO2Bu t<br />
20<br />
OH<br />
FOR PERSONAL USE ONLY<br />
378 Science of Synthesis 4.4 Silicon Compounds<br />
O<br />
TESCl, py, rt, 22 h<br />
82%<br />
OHC<br />
TESO<br />
O<br />
O<br />
Bu t O2C<br />
CO 2Bu t<br />
CO2Bu t<br />
White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg <strong>Thieme</strong> Verlag KG<br />
O<br />
21<br />
OH<br />
O<br />
O
Tri-tert-butyl {1S-[1á,3á,4â,5á,6á(2E,4S,6S),7â]}-4-Hydroxy-6-(1-oxo-4,6-dimethyloct-2enyloxy)-1-(3-oxopropyl)-7-(triethylsiloxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylate<br />
(21): [38]<br />
Alcohol 20 (48.2 mg, 71.9 ìmol) was dissolved in pyridine (2.5 mL), and the soln was<br />
cooled to 08C. A soln of TESCl (0.40 mL, 2.4 mmol) in pyridine (2.0 mL) was added over<br />
5 min, after which the ice bath was removed and the soln was stirred at rt for 22 h. The<br />
mixture was diluted with Et 2O (30 mL) and was washed with 0.5 M HCl (2 ” 30 mL), sat. aq<br />
NaHCO 3 (20 mL), H 2O (20 mL), and brine (20 mL). The aqueous layers were back-extracted<br />
with Et 2O (30 mL), and the combined organic layers were dried (MgSO 4), filtered, and<br />
evaporated. The crude product was purified by flash chromatography (silica gel, gradient<br />
elution, EtOAc/hexanes 1:7 to 1:5) to give 21; yield: 46.3 mg (82%).<br />
4.4.17.2.1.2 Variation 2:<br />
With Chlorotriethylsilane in the Presence of4-(Dimethylamino)pyridine<br />
Chlorotriethylsilane together with 4-(dimethylamino)pyridine is often used for the silylation<br />
of sterically hindered secondary alcohols. [36] This combination with imidazole in dichloromethane<br />
at low temperature was effective in promoting a selective silylation of<br />
one of the two secondary alcohols in compound 22 to yield the mono(triethylsilyl ether)<br />
23 (Scheme 11). [39] This selectivity, which was critical to a subsequent internal ketalization<br />
involving the free hydroxy group of 23, reflects the subtle steric factors that can impinge<br />
upon and differentiate the reactivity of cyclic and acyclic alcohols toward this silylating<br />
agent.<br />
Scheme 11 <strong>Silyl</strong>ation with Chlorotriethylsilane in the Presence of 4-(Dimethylamino)pyridine<br />
[39]<br />
O<br />
OH<br />
O O O<br />
H H H O O<br />
HO MeO<br />
22<br />
FOR PERSONAL USE ONLY<br />
4.4.17 <strong>Silyl</strong> <strong>Ethers</strong> 379<br />
O<br />
TESCl, DMAP, imidazole<br />
CH2Cl2, −78 oC, 3 h<br />
98%<br />
OTES<br />
O O O<br />
H H H O O<br />
HO MeO<br />
(2S,2¢R,2¢¢R,3¢¢R,4¢¢R,5¢S,5¢¢S)-5¢¢-[(1R,2R,3S,4R)-1-Hydroxy-3-methoxy-2-methyl-4-(2-methyl-<br />
1,3-dioxolan-2-yl)pentyl]-2,3¢¢,5¢-trimethyl-4¢¢-(triethylsiloxy)decahydro-2,2¢:5¢,2¢¢-terfuran-5(2H)-one<br />
(23): [39]<br />
To a soln of alcohol 22 (210 mg, 420 ìmol) in CH 2Cl 2 (8.4 mL) at ±788C were added imidazole<br />
(71 mg, 1.05 mmol), DMAP (10 mg), and TESCl (78 ìL, 70 mg, 462 ìmol). After 3 h at<br />
±78 8C, the mixture was quenched by the addition of sat. aq NaHCO 3 (5 mL), and warmed<br />
to rt. The mixture was poured into EtOAc (25 mL) and then sat. aq NaHCO 3 (25 mL). The<br />
phases were separated, and the aqueous layer was extracted with EtOAc (2 ” 25 mL). The<br />
combined organic layers were dried (Na 2SO 4), filtered, and concentrated in vacuo. Purification<br />
by flash chromatography (EtOAc/hexane 45:55) afforded 23 as a clear oil; yield:<br />
253 mg (98%).<br />
23<br />
for references see p 410<br />
White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg <strong>Thieme</strong> Verlag KG
4.4.17.2.2 Method 2:<br />
<strong>Silyl</strong>ation ofAlcohols with Triethylsilyl Trifluoromethanesulfonate<br />
Triethylsilyl trifluoromethanesulfonate (TESOTf) [40] is now available commercially. It is often<br />
employed for the triethylsilylation of less reactive alcohols and is invariably used in<br />
the presence of pyridine or a substituted pyridine. The conversion of alcohol 24 into its<br />
triethylsilyl ether 25, an intermediate in a route to various macrolides, illustrates an<br />
application of this reagent (Scheme 12). [41] The presence of both triethylsilyl and triisopropylsilyl<br />
ethers in 25 was a design element that permitted selective cleavage of the triethylsilyl<br />
ether at a later step in the synthesis.<br />
Scheme 12 <strong>Silyl</strong>ation with Triethylsilyl Trifluoromethanesulfonate [41]<br />
O<br />
O<br />
N<br />
O<br />
Bn<br />
24<br />
OH OTIPS<br />
TESOTf, 2,6-lut<br />
CH2Cl2, rt<br />
99%<br />
O<br />
O<br />
N<br />
O<br />
Bn<br />
25<br />
OTES OTIPS<br />
(4R)-4-Benzyl-3-[(2R,3S,4R,5R)-2,4-dimethyl-1-oxo-3-(triethylsiloxy)-5-(triisopropylsiloxy)hexyl]oxazolidin-2-one<br />
(25): [41]<br />
To a soln of alcohol 24 (1.835 g, 3.74 mmol) in CH 2Cl 2 (75 mL) at rt was added 2,6-lutidine<br />
(0.653 mL, 5.61 mmol), followed by TESOTf (0.930 mL, 4.11 mmol). The resultant colorless<br />
soln was stirred for 40 min before the addition of sat. aq NaHCO 3 (50 mL). The layers were<br />
separated, and the aqueous layer was extracted with CH 2Cl 2 (2 ” 30 mL). The combined organic<br />
phases were washed with 1 M NaHSO 4 (20 mL), H 2O (20 mL), and brine (20 mL), dried<br />
(Na 2SO 4), filtered, and concentrated in vacuo. The product was purified by flash chromatography<br />
(5 ” 15 cm silica gel column, EtOAc/hexanes 1:9) to give 25 as a clear colorless<br />
oil; yield: 2.28 g (99%).<br />
Cleavage<br />
FOR PERSONAL USE ONLY<br />
380 Science of Synthesis 4.4 Silicon Compounds<br />
4.4.17.2.3 Method 3:<br />
Cleavage ofTriethylsilyl <strong>Ethers</strong> under Acidic Conditions<br />
Although triethylsilyl ethers are more stable toward acidic reagents than their trimethylsilyl<br />
counterparts, [42] they can be cleaved under acidic conditions to give the parent alcohol<br />
in good yield. Hydrogen fluoride±pyridine complex is a commonly used reagent for<br />
accomplishing this cleavage, and is often selective, as the example in Scheme 13 illustrates.<br />
Thus, the triethylsilyl ether of 26 was removed in the presence of hydrogen fluoride±pyridine<br />
complex without affecting either the triisopropylsilyl ether or the benzylidene<br />
acetal in this structure. [41] The resultant alcohol 27 was obtained in nearly quantitative<br />
yield.<br />
White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg <strong>Thieme</strong> Verlag KG
Scheme 13 Cleavage of a Triethylsilyl Ether with Hydrogen Fluoride±Pyridine Complex [41]<br />
O<br />
O<br />
N<br />
O<br />
Bn<br />
O<br />
Ph<br />
O<br />
26<br />
O OTES OTIPS<br />
O<br />
O<br />
N<br />
O<br />
Bn<br />
O<br />
HF•py, py, THF, 0 oC 95%<br />
Ph<br />
O<br />
27<br />
O OH OTIPS<br />
(4R)-4-Benzyl-3-[(2R)-2-{(2S,4S,5R,6S)-6-[(1S,5R,6S,7R,8R)-6-hydroxy-1,5,7-trimethyl-3-methylene-4-oxo-8-(triisopropylsiloxy)nonyl]-5-methyl-2-phenyl-1,3-dioxan-4-yl}-1-oxopropyl]oxazolidin-2-one<br />
(27): [41]<br />
To a soln of 26 (162.5 mg, 0.180 mmol) in THF (5 mL) at 0 8C in a Nalgene bottle was added<br />
ca. 4 mL of a HF·pyridine stock soln [HF·pyridine (2 mL), pyridine (4 mL), and THF (16 mL)].<br />
After 2.5 h, the reaction was quenched by the dropwise addition of sat. aq NaHCO 3<br />
(50 mL), and the resultant mixture was stirred at 08C for 30 min. The mixture was then<br />
partitioned between CH 2Cl 2 (10 mL) and H 2O (10 mL). The aqueous layer was separated<br />
and extracted with CH 2Cl 2 (5 ” 10 mL). The combined organic layers were washed with<br />
1 M aq NaHSO 4, dried (Na 2SO 4), filtered, and concentrated in vacuo. The residue was purified<br />
by flash chromatography (2 ” 13.5 cm silica gel column, linear gradient 10 to 20%<br />
EtOAc/hexanes) to afford 27 as a clear colorless oil; yield: 135.2 mg (95%).<br />
4.4.17.2.3.1 Variation 1:<br />
In the Presence of4-Toluenesulfonic Acid<br />
Highly selective cleavage of triethylsilyl ethers can be realized with the acidic catalyst 4toluenesulfonic<br />
acid in the presence of an alcohol such as methanol. [4] For example, the<br />
triethylsilyl ether 28 undergoes cleavage using these conditions without affecting the<br />
methoxymethyl, tert-butyldimethylsilyl, or 4-methoxybenzyl ethers present in this structure<br />
(Scheme 14). The resultant alcohol 29 is a pivotal intermediate in Marshall s synthesis<br />
of discodermolide. [43]<br />
Scheme 14 Cleavage of Triethylsilyl <strong>Ethers</strong> Using 4-Toluenesulfonic Acid as a Catalyst [43]<br />
O<br />
OPMB OTBDMS OMOM<br />
O<br />
FOR PERSONAL USE ONLY<br />
4.4.17 <strong>Silyl</strong> <strong>Ethers</strong> 381<br />
OMOM<br />
28<br />
OPMB OTBDMS OMOM<br />
OPMB OTES<br />
OMOM<br />
29<br />
OPMB OH<br />
TsOH, MeOH<br />
0 oC, 1 h<br />
72%<br />
for references see p 410<br />
White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg <strong>Thieme</strong> Verlag KG
(3R,4S,5R,6S,8S,9Z,11S,12S,13S,14Z,17S,18R,19R,20S,21S,22E)-6-(tert-Butyldimethylsiloxy)-20-hydroxy-4,18-bis(4-methoxybenzyloxy)-8,12-bis(methoxymethoxy)-<br />
3,5,11,13,15,17,19,21-octamethylpentacosa-9,14,22,24-tetraen-2-one (29): [43]<br />
To a cold (0 8C) soln of triethylsilyl ether 28 (40 mg, 0.035 mmol) in MeOH (5 mL) was<br />
added TsOH·H 2O (ca. 2 mg, 0.010 mmol). The resultant mixture was stirred for 1 h at 0 8C.<br />
Et 3N (2 mL) was added, and the mixture was concentrated under reduced pressure. The<br />
residue was purified by flash chromatography (hexanes/EtOAc 4:1 to 2:1) to provide alcohol<br />
29 as a clear oil; yield: 26 mg (72%).<br />
4.4.17.2.3.2 Variation 2:<br />
With Trifluoromethanesulfonic Acid<br />
Aqueous trifluoromethanesulfonic acid has been used to cleave a triethylsilyl ether with<br />
high selectivity, as in the conversion of 30 into the calicheamicinone precursor 31<br />
(Scheme 15). [44] Neither the tert-butyldimethylsilyl ether nor any other acid-sensitive functionality<br />
was compromised in this process.<br />
Scheme 15 Cleavage of Triethylsilyl <strong>Ethers</strong> with Trifluoromethanesulfonic Acid [44]<br />
BocO<br />
Boc2N<br />
TBDMSO O<br />
30<br />
OTES<br />
FOR PERSONAL USE ONLY<br />
382 Science of Synthesis 4.4 Silicon Compounds<br />
TfOH, H2O, THF, rt<br />
95%<br />
BocO<br />
Boc2N TBDMSO O<br />
10-[Bis(tert-butoxycarbonyl)amino]-11-(tert-butoxycarbonyloxy)-1-(tert-butyldimethylsiloxy)-8â-hydroxybicyclo[7.3.1]trideca-4,9,11-triene-2,6-diyn-13-one<br />
(31): [44]<br />
To a soln of 30 (906 mg, 1.17 mmol) in THF (10.6 mL) under argon at rt was added dropwise<br />
a soln of TfOH (1.37 mL) in H 2O (3.87 mL) by cannula with stirring. The mixture was stirred<br />
for 10 min, diluted with Et 2O (50 mL), and washed with sat. aq NaHCO 3 (20 mL). After drying<br />
(MgSO 4) and evaporation of the solvents in vacuo, the product was purified by chromatography<br />
(silica gel, Et 2O/hexanes 2:8) to give 31; yield: 730 mg (95%).<br />
4.4.17.2.4 Method 4:<br />
Cleavage ofTriethylsilyl <strong>Ethers</strong> with Tetrabutylammonium Fluoride<br />
Triethylsilyl ethers are appreciably more stable to basic reagents than trimethylsilyl<br />
ethers and will survive conditions such as potassium carbonate in methanol; [41] however,<br />
they are readily cleaved with tetrabutylammonium fluoride in tetrahydrofuran. The rate<br />
of cleavage with this reagent is sufficiently rapid such that a triethylsilyl group can be removed<br />
without perturbing a more resistant ether, such as a tert-butyldiphenylsilyl ether.<br />
This is illustrated in the selective cleavage of the triethylsilyl ether in 32 to give alcohol<br />
33, in which the tert-butyldiphenylsilyl ether as well as the 4-methoxybenzyl ether are retained<br />
(Scheme 16). [45]<br />
White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg <strong>Thieme</strong> Verlag KG<br />
31<br />
OH
Scheme 16 Cleavage of Triethylsilyl <strong>Ethers</strong> with Tetrabutylammonium Fluoride [45]<br />
O<br />
O<br />
OTBDPS<br />
O<br />
MsO<br />
PMBO OTES<br />
32<br />
TBAF, THF, 0 o C, 45 min<br />
94%<br />
O<br />
O<br />
OTBDPS<br />
O<br />
MsO<br />
PMBO OH<br />
(7R)-5-O-(tert-Butyldiphenylsilyl)-7-{(2S)-4-[(2R)-2-hydroxy-4-(4-methoxybenzyloxy)butyl]-2-<br />
(methylsulfonyloxy)pent-4-enyl}-1,2-O-isopropylidene-3,7-anhydro-4,6-dideoxy-d-riboheptitol<br />
(33): [45]<br />
To a soln of 32 (167 mg, 180 ìmol) in THF (8 mL) at 08C was added a soln of 1.0 M TBAF in<br />
THF (270 ìL, 270 ìmol). The soln was stirred at 0 8C for 45 min then diluted with EtOAc<br />
(60 mL), washed with H 2O (10 mL) and brine (10 mL), and the combined aqueous phases<br />
were extracted with EtOAc (10 mL). The combined organic phases were dried (MgSO 4), filtered<br />
and concentrated by rotary evaporation. Flash chromatography (hexanes/EtOAc 2:1)<br />
afforded 33 as a colorless oil; yield: 137 mg (94%).<br />
4.4.17.3 tert-Butyldimethylsilyl <strong>Ethers</strong><br />
The tert-butyldimethylsilyl (TBDMS) group [46] has become extremely popular among synthetic<br />
chemists as a protecting device for alcohols, and is now the most widely used silyl<br />
ether for this purpose. Both tert-butyldimethylsilyl chloride and tert-butyldimethylsilyl<br />
trifluoromethanesulfonate are effective silylating agents for primary alcohols and many<br />
secondary alcohols; tertiary alcohols are often resistant to silylation with these reagents.<br />
A wide variety of conditions has been developed for the preparation of tert-butyldimethylsilyl<br />
ethers, some of which permit selective silylation of seemingly similar hydroxy<br />
functions.<br />
tert-Butyldimethylsilyl ethers are much more stable toward basic reagents than are<br />
trimethylsilyl and triethylsilyl ethers. They are readily cleaved with tetrabutylammonium<br />
fluoride or hydrogen fluoride±pyridine complex, however, and are sometimes removed<br />
in the course of reduction with hydride reagents such as lithium aluminum<br />
hydride and diisobutylaluminum hydride. tert-Butyldimethylsilyl ethers, although less<br />
sensitive toward acidic reagents than their trimethylsilyl counterparts, are nevertheless<br />
quite readily cleaved in the presence of acetic acid or trifluoroacetic acid. This mode of<br />
cleavage of tert-butyldimethylsilyl ethers can have the advantage of avoiding the strongly<br />
basic reaction medium associated with tetrabutylammonium fluoride.<br />
Formation<br />
FOR PERSONAL USE ONLY<br />
4.4.17 <strong>Silyl</strong> <strong>Ethers</strong> 383<br />
4.4.17.3.1 Method 1:<br />
<strong>Silyl</strong>ation ofAlcohols with tert-Butyldimethylsilyl Chloride<br />
A widely employed method for the preparation of tert-butyldimethylsilyl ethers utilizes<br />
tert-butyldimethylsilyl chloride (TBDMSCl) together with imidazole in dimethylformamide<br />
at temperatures ranging from ambient to 808C. [46] Primary alcohols are readily silylated<br />
under these conditions, as exemplified in the conversion of the triol 34 into the<br />
tris(tert-butyldimethylsilyl ether) 35 (Scheme 17). [47]<br />
33<br />
for references see p 410<br />
White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg <strong>Thieme</strong> Verlag KG
Scheme 17 <strong>Silyl</strong>ation with tert-Butyldimethylsilyl Chloride and Imidazole [47]<br />
HO<br />
O<br />
NMe 2<br />
34<br />
OH<br />
OH<br />
TBDMSCl, imidazole<br />
DMF, 70 oC 94%<br />
TBDMSO<br />
O<br />
NMe 2<br />
35<br />
OTBDMS<br />
OTBDMS<br />
(4S,5E)-9-(tert-Butyldimethylsiloxy)-4,8-bis(tert-butyldimethylsiloxymethyl)-N,N,4-trimethylnon-5-enamide<br />
(35): [47]<br />
A mixture of the triol 34 (100 mg, 0.366 mmol), imidazole (177 mg, 2.6 mmol), and<br />
TBDMSCl (200 mg, 1.3 mmol) in dry DMF (5 mL) was kept at 70 8C overnight. The mixture<br />
was partitioned between Et 2O and H 2O, and the ethereal soln was washed thoroughly<br />
with H 2O, dried (MgSO 4), and evaporated. Purification on silica gel (Et 2O) afforded 35 as a<br />
colorless liquid; yield: 214 mg (94%).<br />
4.4.17.3.1.1 Variation 1:<br />
In the Presence of4-(Dimethylamino)pyridine<br />
<strong>Silyl</strong>ation of more sterically hindered alcohols, such as 36, with tert-butyldimethylsilyl<br />
chloride requires replacement of imidazole (Section 4.4.17.3.1) with a stronger base such<br />
as 4-(dimethylamino)pyridine. [48] Under these conditions, 36 can be converted into its tertbutyldimethylsilyl<br />
ether 37 in high yield (Scheme 18). [49]<br />
Scheme 18 <strong>Silyl</strong>ation with tert-Butyldimethylsilyl Chloride in the Presence<br />
of 4-(Dimethylamino)pyridine [49]<br />
H<br />
HO<br />
36<br />
CN<br />
TBDMSCl, DMAP<br />
DMF, 21<br />
81%<br />
oC, 3 d<br />
H<br />
TBDMSO<br />
rac-(5R)-5-[(1R,2E)-1-(tert-Butyldimethylsiloxy)penta-2,4-dienyl]-2,6,6-trimethylcyclohex-1eneacetonitrile<br />
(37): [49]<br />
To a soln of alcohol 36 (213 mg, 0.87 mmol) in dry DMF (5 mL) was added sequentially<br />
TBDMSCl (170 mg, 1.13 mmol) and DMAP (270 mg, 2.21 mmol). The resulting soln was<br />
stirred at 21 8C for 3 d. H 2O was added, the mixture was extracted with Et 2O, and the combined<br />
extracts were washed with brine, dried, and concentrated. The residual oil was<br />
chromatographed (petroleum ether/Et 2O 19:1) to give 37; yield: 254 mg (81%).<br />
4.4.17.3.1.2 Variation 2:<br />
In Dichloromethane<br />
FOR PERSONAL USE ONLY<br />
384 Science of Synthesis 4.4 Silicon Compounds<br />
Replacement of dimethylformamide as the solvent (Section 4.4.17.3.1.1) by dichloromethane<br />
has the effect of moderating the reactivity of tert-butyldimethylsilyl chloride, so that<br />
the reagent becomes more selective in silylation of alcohols. Thus, the primary alcohol of<br />
38 was protected as its tert-butyldimethylsilyl ether 39 in the course of work on lankacyclins<br />
by using dichloromethane as the solvent (Scheme 19). [50] An advantage of dichloromethane<br />
over dimethylformamide is its easier removal from the product, but since imi-<br />
White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg <strong>Thieme</strong> Verlag KG<br />
37<br />
CN
dazole has diminished solubility in dichloromethane alternative bases, usually 4-(dimethylamino)pyridine<br />
or triethylamine, or sometimes both as in this case, are necessary to<br />
achieve a sufficiently reactive silylating agent.<br />
Scheme 19 <strong>Silyl</strong>ation with tert-Butyldimethylsilyl Chloride in Dichloromethane [50]<br />
OH<br />
CO 2Me<br />
OH<br />
38<br />
TBDMSCl, Et3N<br />
DMAP, CH2Cl2 73%<br />
TBDMSO<br />
39<br />
CO 2Me<br />
Methyl (3S)-4-(tert-Butyldimethylsiloxy)-3-hydroxybutanoate (39): [50]<br />
Et 3N (16 g, 0.158 mol), DMAP (0.6 g, 4.9 mmol) and TBDMSCl (20 g, 0.133 mol) were added<br />
to a soln of dihydroxy ester 38 (16.2 g, 0.121 mol) in CH 2Cl 2 (150 mL). The mixture was<br />
stirred overnight then poured into H 2O. The two phases were separated and the aqueous<br />
layer was extracted with CH 2Cl 2. The combined organic extracts were dried (MgSO 4) and<br />
concentrated under reduced pressure. Chromatography of the residue gave 39 as an oil;<br />
yield: 22 g (73%).<br />
4.4.17.3.2 Method 2:<br />
<strong>Silyl</strong>ation ofAlcohols with tert-Butyldimethylsilyl<br />
Trifluoromethanesulfonate<br />
The more powerful silylating agent tert-butyldimethylsilyl trifluoromethanesulfonate<br />
(tert-butyldimethylsilyl triflate, TBDMSOTf) has become widely used for the preparation<br />
of tert-butyldimethylsilyl ethers in spite of the fact that it is more susceptible to degradation<br />
by moisture than tert-butyldimethylsilyl chloride and has a shorter storage lifetime.<br />
[51] One reason for the popularity of this reagent is that whereas silylation of alcohols<br />
can take many hours with tert-butyldimethylsilyl chloride, even with an excess of that reagent,<br />
it occurs in minutes with tert-butyldimethylsilyl trifluoromethanesulfonate. As a<br />
result, silylation with tert-butyldimethylsilyl trifluoromethanesulfonate can be carried<br />
out at low temperature, a feature that is used to advantage in selective silylation of two<br />
or more hydroxy groups in different steric environments. Thus, exposure of the steroidal<br />
diol 40 to tert-butyldimethylsilyl trifluoromethanesulfonate in the presence of pyridine<br />
at ±78 8C results in virtually instantaneous silylation of the 3-hydroxy substituent to give<br />
41 whilst leaving the D-ring hydroxy untouched (Scheme 20). [52] As in this example, silylation<br />
with tert-butyldimethylsilyl trifluoromethanesulfonate is almost always carried out<br />
in dichloromethane as the solvent.<br />
Scheme 20 <strong>Silyl</strong>ation with tert-Butyldimethylsilyl Trifluoromethanesulfonate [52]<br />
HO<br />
H<br />
40<br />
H<br />
H H<br />
FOR PERSONAL USE ONLY<br />
4.4.17 <strong>Silyl</strong> <strong>Ethers</strong> 385<br />
Ac<br />
OH<br />
TBDMSOTf<br />
py, CH2Cl2, −78 oC 90%<br />
OH<br />
TBDMSO<br />
H<br />
41<br />
H<br />
H H<br />
3â-(tert-Butyldimethylsiloxy)-15â-hydroxy-5á-pregn-16-en-20-one (41): [52]<br />
To a soln of diol 40 (300 mg, 0.9 mmol) in pyridine (5 mL) and CH 2Cl 2 (5 mL) cooled to<br />
±78 8C was added dropwise a soln of TBDMSOTf (0.23 mL, 0.9 mmol) in CH 2Cl 2 (2 mL). Additional<br />
TBDMSOTf in CH 2Cl 2 soln was added (0.1 equiv at a time) until the reaction was<br />
Ac<br />
OH<br />
for references see p 410<br />
White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg <strong>Thieme</strong> Verlag KG
complete. The reaction was quenched at ±788C by the addition of a sat. NH 4Cl soln. The<br />
aqueous layer was extracted with EtOAc, and the extract was concentrated under vacuum.<br />
Purification of the residue by flash chromatography (silica gel, hexane/EtOAc 3:1)<br />
gave 41 as a white solid; yield: 363 mg (90%).<br />
4.4.17.3.2.1 Variation 1:<br />
Selective <strong>Silyl</strong>ation ofPhenols<br />
<strong>Silyl</strong>ation with tert-butyldimethylsilyl trifluoromethanesulfonate at low temperature can<br />
be used to discriminate between phenols and aliphatic hydroxy functions, as in the conversion<br />
of 42 into the aryl silyl ether 43 (Scheme 21). [53] This reaction illustrates the general<br />
observation that phenols are converted into their tert-butyldimethylsilyl ethers more<br />
rapidly than are aliphatic alcohols.<br />
Scheme 21 Selective <strong>Silyl</strong>ation, with tert-Butyldimethylsilyl Trifluoromethanesulfonate, of<br />
a Phenol in the Presence of an Aliphatic Alcohol [53]<br />
MeO<br />
OBn<br />
OMe<br />
O<br />
42<br />
4'<br />
OH<br />
FOR PERSONAL USE ONLY<br />
386 Science of Synthesis 4.4 Silicon Compounds<br />
OH<br />
TBDMSOTf, 2,6-lut, CH 2Cl2, −78 o C, 5 min<br />
90% (2 steps from the 4'-OMEM derivative)<br />
MeO<br />
OBn<br />
OMe<br />
O<br />
43<br />
OH<br />
OTBDMS<br />
(1R)-1-[(2R,3S)-9-Benzyloxy-4-(tert-butyldimethylsiloxy)-6,7-dimethoxy-2,3,8-trimethyl-2,3dihydronaphtho[1,2-b]furan-3-yl]-4-methylpent-3-en-1-ol<br />
(43): [53]<br />
The crude diol 42 (16 mg, prepared in situ from the 4¢-OMEM derivative) was dissolved in<br />
CH 2Cl 2 (1 mL), to which was added 2,6-lutidine (26.1 mg, 0.24 mmol) and TBDMSOTf<br />
(38.1 mg, 0.14 mmol) at ±788C. After the soln was stirred for 5 min, the reaction was<br />
quenched by adding pH 7 phosphate buffer, and the products were extracted with EtOAc.<br />
The combined organic extracts were washed with brine, dried (Na 2SO 4), and concentrated<br />
in vacuo. The residue was purified by preparative TLC (hexane/EtOAc 7:3) to give aryl silyl<br />
ether 43 as a pale yellow oil; yield: 13.0 mg (90% for 2 steps from the 4¢-OMEM derivative).<br />
4.4.17.3.2.2 Variation 2:<br />
Selective <strong>Silyl</strong>ation ofAlcohols<br />
The effect of reaction temperature on selectivity in silylation with tert-butyldimethylsilyl<br />
trifluoromethanesulfonate can be striking, as seen in the conversion of triol 44 into the<br />
bis(tert-butyldimethylsilyl ether) 45 at ±208C (Scheme 22). [54] Although both secondary hydroxy<br />
groups in this cis-fused decahydronaphthalene are equatorial, only the alcohol that<br />
is remote from the quaternary center is silylated. In structures such as 44, where two hydroxy<br />
substituents are in spatial proximity, the initial silylation of one hydroxy group will<br />
often retard reaction of the second hydroxy with this silylating agent, due to steric reasons.<br />
This will, of course, augment selectivity arising from a temperature effect.<br />
White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg <strong>Thieme</strong> Verlag KG
Scheme 22 Selective <strong>Silyl</strong>ation of Secondary Alcohols with tert-Butyldimethylsilyl Trifluoromethanesulfonate<br />
[54]<br />
HO<br />
HO OH<br />
H<br />
H<br />
TBDMSOTf, Et3N<br />
DMAP, CH2Cl2 −20<br />
87%<br />
oC, 30 min<br />
TBDMSO<br />
44 45<br />
HO OTBDMS<br />
H<br />
(1á,3â,4aá,5á,8â,8aá)-8-(tert-Butyldimethylsiloxy)-3-(tert-butyldimethylsiloxymethyl)-5isopropyl-3-methyldecahydro-1-naphthol<br />
(45): [54]<br />
To a stirred mixture of triol 44 (92 mg, 0.36 mmol), Et 3N (109 mg, 1.08 mmol), and DMAP<br />
(2 mg, 0.016 mmol) in CH 2Cl 2 (5 mL) at ±20 8C, was added TBDMSOTf (190 mg, 0.72 mmol).<br />
The mixture was stirred at ±208C for 30 min, diluted with Et 2O (40 mL), washed with 5%<br />
HCl (2 mL), brine (5 mL) and H 2O (5 mL), dried (Na 2SO 4), and concentrated in vacuo. Flash<br />
chromatography of the residue (silica gel, EtOAc/hexane 5:95) afforded 45 as a colorless<br />
oil; yield: 152 mg (87%).<br />
4.4.17.3.3 Method 3:<br />
Migration ofa tert-Butyldimethylsilyl Group from<br />
a tert-Butyldimethylsilyl Ether to an Alcohol<br />
The tert-butyldimethylsilyl group of a tert-butyldimethylsilyl ether will migrate to the oxygen<br />
atom of an adjacent alcohol under basic conditions if the new tert-butyldimethylsilyl<br />
ether is sterically less crowded than its precursor. [14] Thus, the direction of migration is<br />
invariably from a secondary to a primary alcohol or from a tertiary to either a secondary<br />
or primary alcohol. Migration between 1,2-substituted and 1,3-substituted diol derivatives<br />
is particularly common, although transfer of a tert-butyldimethylsilyl group between<br />
oxygens that span four or more carbons can occur if the oxygens are in spatial<br />
proximity. [16] The mechanism usually envisioned for these migrations involves intramolecular<br />
attack by an alkoxide oxygen on silicon to produce a pentacoordinate intermediate<br />
that collapses toward the more thermodynamically stable tert-butyldimethylsilyl<br />
ether. While silyl migration between oxygen atoms can pose an inconvenience in certain<br />
polyhydroxylated systems such as carbohydrates, where site-specific silylation may be desired,<br />
a virtue can be made of this chemistry in the deprotection of a silyl ether that may<br />
be difficult to cleave. Thus, if the silyl group can be forced to move to a less sterically<br />
crowded oxygen, its cleavage can become more facile.<br />
An example of an efficient migration of a tert-butyldimethylsilyl group is seen in the<br />
rearrangement of secondary tert-butyldimethylsilyl ether 46 to its isomeric primary silyl<br />
ether 47 (Scheme 23). [55]<br />
Scheme 23 Rearrangement of a Secondary tert-Butyldimethylsilyl Ether<br />
to a Primary tert-Butyldimethylsilyl Ether [55]<br />
OTBDMS<br />
F3C OH<br />
46<br />
FOR PERSONAL USE ONLY<br />
4.4.17 <strong>Silyl</strong> <strong>Ethers</strong> 387<br />
t-BuOK, THF/DMF (1:4)<br />
−78 oC, 4 h<br />
99%<br />
OH<br />
47<br />
H<br />
F 3C OTBDMS<br />
Another example, in this case involving migration of the tert-butyldimethylsilyl group<br />
from a tertiary to a secondary alcohol, occurred in the course of an approach to the core<br />
structure of esperamicin A. [56] The rearrangement was triggered by S,S-diphenylsulfil-<br />
for references see p 410<br />
White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg <strong>Thieme</strong> Verlag KG
imine used for the elaboration of the aziridine 49 from á,â-unsaturated ketone 48<br />
(Scheme 24).<br />
Scheme 24 Migration of a tert-Butyldimethylsilyl Group to a Secondary Alcohol [56]<br />
HO<br />
TBDMSO<br />
O<br />
Ph 2S NH H 2O<br />
CH2Cl 2, rt, 16 h<br />
60%<br />
TBDMSO<br />
HO<br />
MeO<br />
H<br />
MeO<br />
48 49<br />
4-(tert-Butyldimethylsiloxy)-1,1,1-trifluorobutan-2-ol (47): [55]<br />
A 0.5 M soln of alcohol 46 in a mixed solvent of THF and DMF (1:4) was reacted with t-<br />
BuOK (1.1 equiv) at ±788C. After stirring for 4 h at that temperature, the reaction was<br />
quenched with aq NH 4Cl and extracted with Et 2O (3 ”). The combined extracts were dried<br />
(MgSO 4), filtered, concentrated in vacuo, and purified by column chromatography<br />
(EtOAc/hexanes 14:86) to afford 47 in quantitative yield.<br />
(+)-(1S,8S,9S,10S,12R)-12-(tert-Butyldimethylsiloxy)-1-hydroxy-9,10-imino-8-methoxybicyclo[7.3.1]tridec-4-ene-2,6-diyn-11-one<br />
(49): [56]<br />
To a soln of ketol 48 (59 mg, 0.16 mmol) in dry CH 2Cl 2 (5 mL) was added S,S-diphenylsulfilimine<br />
monohydrate (359 mg, 1.64 mmol), and the resulting suspension was stirred at rt<br />
for 16 h. The reaction was quenched with sat. NaHCO 3 and extracted with CH 2Cl 2 (3 ”).<br />
The combined organics were washed with H 2O (2 ”) and brine (1 ”), dried (Na 2SO 4), filtered,<br />
and concentrated. The resulting crude material was subjected to flash chromatography<br />
(Et 2O/heptane 1:1) to give aziridine 49 as white needles; yield: 36 mg (60%).<br />
Cleavage<br />
FOR PERSONAL USE ONLY<br />
388 Science of Synthesis 4.4 Silicon Compounds<br />
4.4.17.3.4 Method 4:<br />
Cleavage of tert-Butyldimethylsilyl <strong>Ethers</strong> with<br />
Tetrabutylammonium Fluoride<br />
The most general method for cleaving tert-butyldimethylsilyl ethers is with tetrabutylammonium<br />
fluoride in tetrahydrofuran. Unhindered silyl ethers of this class are transformed<br />
quite readily to their respective alcohols with this reagent at room temperature.<br />
[46] Conversion of the bis(tert-butyldimethylsilyl ether) 50 into diol 51 illustrates this<br />
cleavage and demonstrates that a tert-butyldiphenylsilyl ether can be retained intact under<br />
these conditions (Scheme 25). [57]<br />
White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg <strong>Thieme</strong> Verlag KG<br />
O<br />
HN<br />
H
Scheme 25 Cleavage of Primary and Secondary tert-Butyldimethylsilyl <strong>Ethers</strong> with Tetrabutylammonium<br />
Fluoride [57]<br />
TBDPSO<br />
MeO<br />
TBDMSO<br />
NBoc O<br />
OTBDMS<br />
O<br />
50<br />
O<br />
OMe<br />
O O O<br />
OMe<br />
O<br />
TBAF, THF, rt, 2 h<br />
71%<br />
TBDPSO<br />
MeO<br />
HO<br />
OH<br />
NBoc O<br />
O<br />
51<br />
O<br />
OMe<br />
O O O<br />
More sterically crowded tert-butyldimethylsilyl ethers are sometimes stable toward tetrabutylammonium<br />
fluoride. For example, the tris(silyl ether) 52 undergoes selective cleavage<br />
of only one of the three secondary ether functions with tetrabutylammonium fluoride<br />
to afford hydroxy acid 53 (Scheme 26). [58] A possible explanation for this selectivity<br />
is intramolecular transfer of the most remote tert-butyldimethylsilyl group to the carboxylate<br />
formed when 52 is exposed to the basic fluoride reagent; subsequent acidic<br />
hydrolysis of the silyl ester would lead to 53.<br />
Scheme 26 Selective Cleavage of a tert-Butyldimethylsilyl Ether with Tetrabutylammonium<br />
Fluoride [58]<br />
TBDMSO<br />
FOR PERSONAL USE ONLY<br />
4.4.17 <strong>Silyl</strong> <strong>Ethers</strong> 389<br />
OTBDMS<br />
CO2H O OTBDMS<br />
52<br />
S<br />
N<br />
TBDMSO<br />
TBAF, THF<br />
25 oC, 8 h<br />
78%<br />
OH<br />
CO2H<br />
O OTBDMS<br />
53<br />
OMe<br />
S<br />
N<br />
O<br />
for references see p 410<br />
White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg <strong>Thieme</strong> Verlag KG
(4S,6R)-4-[(1R,2S,3E)-2-{[1-(tert-Butoxycarbonyl)-2-piperidyl]carbonyloxy}-4-[(1R,3R,4R)-4-<br />
(tert-butyldiphenylsiloxy)-3-methoxycyclohexyl]-1,3-dimethylbut-3-enyl]-11-[(1E,4S,6S)-6-<br />
{(2R,3S,5R,6R)-6-[(1S)-1,2-dihydroxyethyl]-3-methoxy-5-methyltetrahydropyran-2-yl}-6methoxy-2,4-dimethylhex-1-enyl]-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-10-en-9-one<br />
(51): [57]<br />
To a soln of bis(tert-butyldimethylsilyl ether) 50 (879 mg, 0.61 mmol) in THF (15 mL) was<br />
added 1 M TBAF in THF (1.84 mL, 1.84 mmol). After 2 h, the reaction was quenched with<br />
NH 4Cl, and the THF was removed in vacuo. The product was extracted into EtOAc, and<br />
the organic extracts were dried (MgSO 4), filtered, and concentrated in vacuo. The residue<br />
was chromatographed (silica gel, 20±50% EtOAc/hexanes) to give diol 51; yield: 525 mg<br />
(71%).<br />
(3S,6R,7S,12Z,15S,16E)-3,7-Bis(tert-butyldimethylsiloxy)-15-hydroxy-4,4,6,16-tetramethyl-<br />
17-(2-methyl-1,3-thiazol-4-yl)-5-oxoheptadeca-12,16-dienoic Acid (53): [58]<br />
A soln of tris(tert-butyldimethylsilyl ether) 52 (300 mg, 0.36 mmol) in THF (7.0 mL) at 258C<br />
was treated with 1 M TBAF in THF (2.2 mL, 2.2 mmol, 6.0 equiv). After being stirred for 8 h,<br />
the mixture was diluted with EtOAc (10 mL) and washed with 1 M aq HCl (10 mL). The<br />
aqueous soln was extracted with EtOAc (4 ” 10 mL), and the combined organic phase was<br />
washed with brine (10 mL), dried (MgSO 4), and concentrated. The crude mixture was purified<br />
by flash column chromatography (silica gel, MeOH/CH 2Cl 2 5:95) to provide hydroxy<br />
acid 53 as a yellow oil; yield: 203 mg (78%).<br />
4.4.17.3.5 Method 5:<br />
Cleavage of tert-Butyldimethylsilyl <strong>Ethers</strong> with<br />
Tris(dimethylamino)sulfur (Trimethylsilyl)difluoride<br />
Tris(dimethylamino)sulfur (trimethylsilyl)difluoride (TASF) [59] is a source of fluoride ion<br />
that is sometimes more effective than tetrabutylammonium fluoride (Section 4.4.17.3.4)<br />
for removing silyl ethers, [60] especially where the basicity associated with the latter reagent<br />
presents a problem. Thus, cleavage of the tert-butyldimethylsilyl ether 54 with<br />
tris(dimethylamino)sulfur (trimethylsilyl)difluoride gives the taxol precursor 55 in high<br />
yield (Scheme 27), whereas exposure of 54 to tetrabutylammonium fluoride results in<br />
cleavage of the benzoate as well as the silyl group. [61] Attempts to cleave the silyl ether of<br />
54 with hydrogen fluoride±pyridine complex led to products of rearrangement.<br />
Scheme 27 Cleavage of a tert-Butyldimethylsilyl Ether with Tris(dimethylamino)sulfur<br />
(Trimethylsilyl)difluoride [61]<br />
TBDMSO<br />
AcO<br />
HO<br />
BzO<br />
AcO<br />
54<br />
FOR PERSONAL USE ONLY<br />
390 Science of Synthesis 4.4 Silicon Compounds<br />
O<br />
OBOM<br />
O<br />
TASF, THF, rt, 1 h<br />
94%<br />
HO<br />
AcO<br />
HO<br />
BzO<br />
AcO<br />
55<br />
O<br />
OBOM<br />
7-O-(Benzyloxymethyl)baccatin III (55): [61]<br />
A soln of silyl ether 54 (16.3 mg, 19.9 ìmol) in THF (0.5 mL) was added to TASF (37 mg,<br />
0.134 mmol) at rt under a N 2 atmosphere. The mixture was stirred for 1 h, diluted with<br />
EtOAc, poured into sat. aq NaHCO 3 (20 mL) and extracted with CHCl 3 (3 ” 30 mL). The combined<br />
organic phase was dried (Na 2SO 4) and concentrated under reduced pressure to give<br />
a pale yellow oil (16 mg), which was filtered through a pad of silica gel using EtOAc/hexane<br />
(7:3) as eluent. The filtrate was concentrated to give diol 55; yield: 13.5 mg (94%).<br />
White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg <strong>Thieme</strong> Verlag KG<br />
O
4.4.17.3.6 Method 6:<br />
Cleavage of tert-Butyldimethylsilyl <strong>Ethers</strong> under Acidic Conditions<br />
A wide variety of acidic reagents has been used for the cleavage of tert-butyldimethylsilyl<br />
ethers. Several of these reagents exhibit good selectivity for the removal of a particular<br />
tert-butyldimethylsilyl ether while leaving other silyl ethers, even a trimethylsilyl ether,<br />
intact. For example, exposure of the bis(silyl ether) 56 to hydrofluoric acid in acetonitrile<br />
cleaves the primary tert-butyldimethylsilyl ether but does not alter the angular trimethylsilyl<br />
ether (Scheme 28). [34] The resulting alcohol 57 would have been difficult to obtain<br />
from 56 by other silyl ether cleavage methods; the selectivity observed probably reflects<br />
more facile protonation of the primary ether oxygen.<br />
Scheme 28 Selective Cleavage of a tert-Butyldimethylsilyl Ether with Hydrofluoric Acid [34]<br />
H<br />
O<br />
O OTMS<br />
Ac<br />
56<br />
O<br />
FOR PERSONAL USE ONLY<br />
4.4.17 <strong>Silyl</strong> <strong>Ethers</strong> 391<br />
O<br />
O<br />
49% aq HF<br />
H<br />
O<br />
MeCN, 0<br />
O<br />
o H C, 6 min<br />
H<br />
90%<br />
OTBDMS<br />
O OTMS<br />
(3aR,3bS,5S,6aR,8S,9aS,9bR,10R,11aS)-11a-Acetyl-5,9b-epoxy-5-(hydroxymethyl)-8,10-dimethyl-6a-(trimethylsiloxy)dodecahydroazuleno[5,4-e]-1,3-benzodioxole-2,7(3aH)-dione<br />
(57): [34]<br />
49% Aq HF (4.0 mL) was added dropwise to a soln of the silyl ether 56 (1.30 g, 2.23 mmol) in<br />
MeCN (30 mL) at 08C. After being stirred for 6 min, the mixture was quenched with sat. aq<br />
NaHCO 3 (CAUTION: careful addition was required until the evolution of CO 2 was no longer observed),<br />
diluted with H 2O (150 mL), and extracted with EtOAc (3 ” 100 mL). The combined<br />
organic extracts were dried (MgSO 4), filtered, and concentrated in vacuo. Purification by<br />
flash chromatography (EtOAc/hexanes 1:1) gave the alcohol 57; yield: 0.934 g (90%).<br />
4.4.17.3.6.1 Variation 1:<br />
With Hydrogen Fluoride±Pyridine Complex<br />
Hydrogen fluoride±pyridine complex, a reagent which is often used in a mixed solvent<br />
system comprising pyridine and tetrahydrofuran, is highly effective for the cleavage of<br />
tert-butyldimethylsilyl ethers. [62] In general, primary tert-butyldimethylsilyl ethers are<br />
cleaved much more rapidly than their secondary or tertiary ether counterparts with hydrogen<br />
fluoride±pyridine complex, and selective cleavage is usually possible with this reagent.<br />
Reaction temperature is the critical factor in achieving selective cleavage in these<br />
cases. A representative silyl ether cleavage with hydrogen fluoride±pyridine complex is<br />
the conversion of the chlorothricolide intermediate 58 into the primary alcohol 59<br />
(Scheme 29). [63] None of the other functional or protecting groups of thioester 58 (which<br />
was a mixture of two diastereomers resulting from the convergence of racemic subunits)<br />
are affected by this reagent.<br />
57<br />
Ac<br />
O<br />
OH<br />
O<br />
for references see p 410<br />
White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg <strong>Thieme</strong> Verlag KG
Scheme 29 Cleavage of a tert-Butyldimethylsilyl Ether with Hydrogen Fluoride±Pyridine<br />
Complex [63]<br />
PhS<br />
O<br />
TBDMSO<br />
MeO<br />
O<br />
O<br />
SEMO<br />
H<br />
O<br />
O<br />
H<br />
H OMOM<br />
+ diastereomer<br />
58<br />
PhS<br />
O<br />
HF py, py<br />
THF, rt, 2 h<br />
97%<br />
SEMO<br />
O<br />
HO<br />
MeO<br />
O<br />
H<br />
O<br />
O<br />
H<br />
H OMOM<br />
+ diastereomer<br />
rac-[1á(5S*,6S*,8R*,9R*),2á,4aâ,5â,8aá]-6-(Hydroxymethyl)-4-methoxy-9-methyl-2-oxo-8-<br />
[2-(trimethylsilyl)ethoxymethoxy]-1-oxaspiro[4.5]dec-3-en-3-yl 5-(Methoxymethoxy)-1methyl-2-[4-oxo-4-(phenylsulfanyl)butyl]-1,2,4a,5,6,7,8,8a-octahydronaphthalene-1-carboxylate<br />
(59): [63]<br />
To a rapidly stirred soln of the thioester 58 (mixture of 2 diastereomers; 762 mg,<br />
0.83 mmol) in THF (1 mL) was added a HF x ·pyridine soln [5 mL, prepared by diluting Aldrich<br />
HF x ·pyridine (13 g) with pyridine (31 mL) and THF (100 mL)], and the resulting mixture<br />
was stirred at rt for 2 h. After the mixture was poured into sat. NaHCO 3 (50 mL), the<br />
aqueous layer was extracted with Et 2O (3 ” 100 mL) and the combined organic layers were<br />
dried (MgSO 4). After removal of the solvent at reduced pressure, the crude residue was<br />
chromatographed (size C Lobar silica gel column, EtOAc/petroleum ether 28:72) to give<br />
the ªfasterº eluting alcohol 59 as a colorless oil; yield: 289 mg (43%). Further elution afforded<br />
the diastereomeric alcohol as a colorless oil; yield: 360 mg (54%).<br />
4.4.17.3.6.2 Variation 2:<br />
With Mineral Acid<br />
FOR PERSONAL USE ONLY<br />
392 Science of Synthesis 4.4 Silicon Compounds<br />
A solution of a mineral acid such as hydrochloric acid can accomplish selective cleavage<br />
of certain silyl ethers, including tert-butyldimethylsilyl ethers. [64] An illustration of this selectivity<br />
is seen in the reaction of the differentially protected tetrakis(silyl ether) 60 with<br />
10% hydrochloric acid, which leads to the diol 61 (Scheme 30). [65] Only the trimethylsilyl<br />
and tert-butyldimethylsilyl ethers are cleaved under these conditions, the triisopropylsilyl<br />
and tert-butyldiphenylsilyl ethers being unreactive.<br />
White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg <strong>Thieme</strong> Verlag KG<br />
59
Scheme 30 Selective Cleavage of a tert-Butyldimethylsilyl Ether with Hydrochloric Acid [65]<br />
TIPSO<br />
O<br />
OTMS<br />
TBDPSO<br />
OTBDMS<br />
60<br />
O<br />
O<br />
Pr i<br />
TIPSO<br />
O<br />
10% aq HCl<br />
THF, rt, 3 h<br />
87%<br />
OH<br />
TBDPSO<br />
(3E,3aS,4S,6S,7S,7aR)-3-{(2E,4R,6E)-8-[(2R,4S,8R,9S)-4-(tert-Butyldiphenylsiloxy)-8-isopropyl-9-methyl-1,7-dioxaspiro[5.5]undec-2-yl]-4,6-dimethylocta-2,6-dienylidene}-4-(hydroxymethyl)-6-methyl-7-(triisopropylsiloxy)hexahydrobenzofuran-3a(4H)-ol<br />
(61): [65]<br />
To a soln of tetrakis(silyl ether) 60 (0.41 g, 0.36 mmol) in THF (40 mL) was added 10% aq<br />
HCl (5.5 mL). The mixture was stirred at rt for 3 h and cooled to 0 8C. Solid NaHCO 3 was<br />
added carefully in small portions until all the bubbling subsided. The aqueous layer was<br />
extracted with Et 2O (4 ” 20 mL), and the combined organic extracts were dried (MgSO 4),<br />
filtered, and concentrated in vacuo. Purification of the residue by column chromatography<br />
(silica gel, 5±10% EtOAc/hexanes) provided diol 61 as a white foam; yield: 0.30 g (87%).<br />
4.4.17.3.6.3 Variation 3:<br />
With Organic Acids<br />
Organic acids used for cleavage of tert-butyldimethylsilyl ethers include formic, [66] acetic,<br />
[67] trifluoroacetic, [68] and certain sulfonic acids. [69] Formic acid is the least selective of<br />
these reagents, showing little discrimination in the cleavage of tert-butyldimethylsilyl<br />
ethers in different steric or electronic environments. An example of a deprotection with<br />
this reagent is the reaction of the bis(tert-butyldimethylsilyl ether) 62 to give lankacidin C<br />
(63, Scheme 31). [66]<br />
Scheme 31 Cleavage of tert-Butyldimethylsilyl <strong>Ethers</strong> with Formic Acid [66]<br />
O<br />
O O<br />
TBDMSO OTBDMS<br />
62<br />
O<br />
HN<br />
FOR PERSONAL USE ONLY<br />
4.4.17 <strong>Silyl</strong> <strong>Ethers</strong> 393<br />
O<br />
HCO2H, THF<br />
H2O, rt, 3 h<br />
86%<br />
OH<br />
61<br />
O<br />
O<br />
HN<br />
O O<br />
O<br />
Pr i<br />
HO OH<br />
The use of trifluoroacetic acid for cleavage of tert-butyldimethylsilyl ethers is confined to<br />
compounds that are stable to a moderately strong acid, but the reagent can offer a valuable<br />
means for selective cleavage of these ethers. For example, the bis(tert-butyldimethyl-<br />
63<br />
O<br />
O<br />
for references see p 410<br />
White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg <strong>Thieme</strong> Verlag KG
silyl ether) 64 undergoes selective scission with trifluoroacetic acid, giving alcohol 65 in<br />
high yield (Scheme 32). [70] The more sterically hindered secondary silyl ether of 64 remains<br />
unaffected by this reagent.<br />
Scheme 32 Selective Cleavage of a tert-Butyldimethylsilyl Ether with Trifluoroacetic Acid [70]<br />
MeO<br />
MeO<br />
MeO N<br />
OMe<br />
OMe<br />
64<br />
OTBDMS<br />
OTBDMS<br />
TFA, THF<br />
H2O, 0 oC, 3 h<br />
91%<br />
MeO<br />
MeO<br />
MeO N<br />
OMe<br />
OMe<br />
65<br />
OTBDMS<br />
Selectivity in the cleavage of tert-butyldimethylsilyl ethers can also be achieved with 10camphorsulfonic<br />
acid. Thus, the secondary silyl ether but not the angular silyl ether of<br />
compound 66 is removed with 10-camphorsulfonic acid in dichloromethane containing<br />
a small amount of methanol to afford the diol 67 in excellent yield (Scheme 33). [71]<br />
Scheme 33 Selective Cleavage of a tert-Butyldimethylsilyl Ether with<br />
10-Camphorsulfonic Acid [71]<br />
HO<br />
H<br />
O<br />
OTBDMS<br />
O<br />
OTBDMS<br />
FOR PERSONAL USE ONLY<br />
394 Science of Synthesis 4.4 Silicon Compounds<br />
CSA, CH2Cl2, MeOH, 25 oC, 1 h<br />
100%<br />
HO<br />
66 67<br />
H<br />
O<br />
OH<br />
O<br />
OTBDMS<br />
Lankacidin C (63): [66]<br />
A soln of bis(silyl ether) 62 (15 mg, 0.022 mmol) in a mixture of THF/HCO 2H/H 2O (6:3:1,<br />
2.0 mL) was stirred at rt for 3 h. The mixture was cooled to 08C and neutralized with sat.<br />
aq NaHCO 3 (2 mL). This mixture was poured into EtOAc (10 mL) and brine (10 mL). The<br />
aqueous layer was extracted with EtOAc (10 mL). The combined organic layers were dried<br />
(MgSO 4), filtered, and concentrated in vacuo. Purification by preparative TLC (EtOAc) gave<br />
lankacidin C (63) as a white solid; yield: 8.7 mg (86%).<br />
White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg <strong>Thieme</strong> Verlag KG<br />
OH
(2Z,4S,5R,6E,8S,9R,10S,12S,13R)-5-(tert-Butyldimethylsiloxy)-13-[3-(2,5-dimethyl-1H-pyrrol-1-yl)-2,5-dimethoxyphenyl]-9,10,13-trimethoxy-4,6,8,12-tetramethyltrideca-2,6-dien-<br />
1-ol (65): [70]<br />
A soln of bis(silyl ether) 64 (42 mg, 0.051 mmol) in THF (2 mL) containing TFA/H 2O (9:1,<br />
400 ìL) was stirred at 08C for 3 h. Sat. NaHCO 3 (5 mL) was added, and the mixture was extracted<br />
with Et 2O (3 ” 10 mL). The combined organic layers were dried (MgSO 4) and concentrated<br />
under reduced pressure; the residue was purified by flash chromatography<br />
(hexanes/EtOAc 3:1) to give alcohol 65 as a colorless, viscous oil; yield: 33 mg (91%).<br />
(3aR,4R,5S,7aS)-7a-(tert-Butyldimethylsiloxy)-5-hydroxy-4-(hydroxymethyl)-4-methyl-<br />
3a,4,5,7a-tetrahydroisobenzofuran-1(3H)-one (67): [71]<br />
A soln of alcohol 66 (43.9 g, 99 mmol) in CH 2Cl 2 (250 mL) and MeOH (20 mL) was treated<br />
with CSA (0.52 g, 2.24 mmol) and stirred at 258C for 1 h. After dilution with CH 2Cl 2<br />
(300 mL), the reaction was quenched with aq NaHCO 3 (150 mL). The organic layer was separated,<br />
and the aqueous layer was extracted with Et 2O (2 ” 200 mL). The combined organic<br />
layer was dried (Na 2SO 4), concentrated, and purified by flash chromatography (silica gel,<br />
Et 2O/petroleum ether 1:1) to give diol 67 as white crystals; yield: 32.6 g (100%).<br />
4.4.17.3.6.4 Variation 4:<br />
With Lewis Acids<br />
Lewis acids have found limited use as reagents for cleaving silyl ethers, in part because<br />
they coordinate weakly with the oxygen atom of ethers of this class; however, they can<br />
sometimes effect a remarkably efficient cleavage of a tert-butyldimethylsilyl ether, [72] as<br />
in the conversion of silyl ether 68 into alcohol 69 with boron trifluoride±diethyl ether<br />
complex (Scheme 34). [73] A noteworthy feature of this transformation is that the trisubstituted<br />
epoxide of 68 does not suffer rearrangement to a ketone under the reaction conditions.<br />
Scheme 34 Cleavage of a tert-Butyldimethylsilyl Ether with Boron Trifluoride±Diethyl<br />
Ether Complex [73]<br />
O<br />
BnO<br />
H<br />
H<br />
68<br />
O<br />
O<br />
OTBDMS<br />
FOR PERSONAL USE ONLY<br />
4.4.17 <strong>Silyl</strong> <strong>Ethers</strong> 395<br />
BF3 OEt2, CH2Cl2<br />
0−10 oC 92%<br />
(4aá,8aá,9aá)-1á-Benzyloxy-6á-hydroxy-4á,6aâ,7aâ,9bâ-tetramethyldodecahydrophenanthro[2,3-b]oxirene-2,7-dione<br />
(69): [73]<br />
To a soln of silyl ether 68 (53 mg, 0.10 mmol) in dry CH 2Cl 2 (8 mL) was added BF 3 ·OEt 2<br />
(63 ìL, 0.50 mmol) at 08C under N 2. The mixture was allowed to warm to ca. 108C and<br />
was then stirred for 6 h. The reaction was quenched with sat. aq NH 4Cl (2 mL), and the<br />
aqueous phase was extracted with CH 2Cl 2 (3 ” 10 mL). The combined organic extracts<br />
were washed with brine (2 mL), dried (MgSO 4), and filtered. Concentration of the filtrate<br />
followed by flash column chromatography (hexane/EtOAc 7:1) gave alcohol 69 as a white<br />
solid; yield: 38 mg (92%).<br />
O<br />
BnO<br />
H<br />
69<br />
H<br />
O<br />
OH<br />
O<br />
for references see p 410<br />
White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg <strong>Thieme</strong> Verlag KG
4.4.17.4 Triisopropylsilyl <strong>Ethers</strong><br />
Triisopropylsilyl (TIPS) ethers are used as protection for primary and certain secondary<br />
alcohols, [74] the large steric bulk of the silyl group ensuring good selectivity in most instances.<br />
[75] Secondary alcohols can only be converted into their triisopropylsilyl ethers under<br />
more forcing conditions, and tertiary alcohols in general cannot be converted into triisopropylsilyl<br />
ethers. A principal advantage of triisopropylsilyl ethers is their stability<br />
toward basic conditions which cause cleavage of other functional groupings, including<br />
silyl ethers such as tert-butyldimethylsilyl. [76] Thus, esters can be saponified without destruction<br />
of a triisopropylsilyl ether, and strong bases such as tert-butyllithium, which<br />
can deprotonate the methyl group of a tert-butyldimethylsilyl ether, are without effect<br />
on a triisopropylsilyl ether. The triisopropylsilyl ether is among the weakest of the silyl<br />
ethers in terms of coordination to metal cations. [77] It is advisable not to use an excess of<br />
silylating agent, since it is sometimes contaminated with the more reactive, isomeric diisopropyl(propyl)silyl<br />
reagent. [78]<br />
Formation<br />
4.4.17.4.1 Method 1:<br />
<strong>Silyl</strong>ation ofAlcohols with Triisopropylsilyl<br />
Trifluoromethanesulfonate and 2,6-Lutidine<br />
The large steric demand imposed by the triisopropylsilyl group makes triisopropylsilyl<br />
trifluoromethanesulfonate (TIPSOTf) the most useful reagent for silylations in this class.<br />
In the presence of 2,6-lutidine and with dichloromethane as solvent, it is generally feasible<br />
to convert a primary alcohol into its triisopropylsilyl ether without affecting a secondary<br />
alcohol. [51] The conversion of diol 70 containing a primary and secondary hydroxy substituent<br />
into its mono(silyl ether) 71 reflects the selectivity that can be attained with this<br />
reagent (Scheme 35). [79]<br />
Scheme 35 Selective <strong>Silyl</strong>ation of a Primary Alcohol with<br />
Triisopropylsilyl Trifluoromethanesulfonate [79]<br />
H<br />
O O<br />
70<br />
OH<br />
FOR PERSONAL USE ONLY<br />
396 Science of Synthesis 4.4 Silicon Compounds<br />
HO TIPSO<br />
TIPSOTf, 2,6-lut<br />
CH2Cl2, −8 oC 91%<br />
H<br />
O O<br />
(4aR,5R,6RS,8aR)-6-Hydroxy-5,8a-dimethyl-5-[2-(triisopropylsiloxy)ethyl]octahydronaphthalen-1(2H)-one<br />
Ethylene Ketal (71): [79]<br />
To a soln of the diol 70 (5.28 g, 18 mmol) and 2,6-lutidine (3.15 mL, 27 mmol) in CH 2Cl 2<br />
(25 mL) was added a soln of TIPSOTf (4.85 mL, 18 mmol) in CH 2Cl 2 (5 mL) over 1 h at ±88C.<br />
After the mixture had been stirred for 4 h, the reaction was quenched by the addition of<br />
aq NaHCO 3. After separation of the organic layer, the aqueous layer was extracted with<br />
EtOAc (2 ”). The combined extracts were washed with brine and evaporated to dryness.<br />
The residue was purified by column chromatography (silica gel, hexane/EtOAc 5:1) to<br />
give alcohol 71; yield: 7.47 g (91%).<br />
White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg <strong>Thieme</strong> Verlag KG<br />
71<br />
OH
4.4.17.4.1.1 Variation 1:<br />
With Triisopropylsilyl Trifluoromethanesulfonate<br />
in the Presence of4-(Dimethylamino)pyridine<br />
As with other silylating agents, triisopropylsilyl trifluoromethanesulfonate becomes<br />
more reactive when used in the presence of 4-(dimethylamino)pyridine, especially when<br />
pyridine is the solvent. Under these conditions, secondary alcohols are converted into<br />
their triisopropylsilyl ethers rapidly and in high yield. The silylation of diol 72 to give<br />
the tris(silyl ether) 73 illustrates this increased reactivity of the silylating agent (Scheme<br />
36). [80]<br />
Scheme 36 <strong>Silyl</strong>ation of Secondary Alcohols with Triisopropylsilyl Trifluoromethanesulfonate<br />
[80]<br />
TBDPSO<br />
HO<br />
HO<br />
H<br />
O<br />
72<br />
O<br />
O<br />
O<br />
O<br />
TBDPSO<br />
TIPSO<br />
TIPSOTf<br />
DMAP, py, rt, 15 h<br />
99%<br />
TIPSO<br />
(1S,1¢S,3R,5S,5¢S,6S,6¢S)-8-[(1S,3R)-4-(tert-Butyldiphenylsiloxy)-1,3-bis(triisopropylsiloxy)butyl]-5,5¢-dimethyl-8¢-oxo-3,3¢-spirobi(2,7-dioxabicyclo[4.3.0]nonane)<br />
(73): [80]<br />
Diol 72 (125 mg, 0.200 mmol) was combined with DMAP (44 mg, 0.36 mmol) under a N 2<br />
atmosphere and then dissolved in dry pyridine (0.6 mL). TIPSOTf (0.4 mL, 1.49 mmol) was<br />
added via syringe, and the mixture was stirred for 15 h. Excess TIPSOTf was consumed by<br />
the addition of dry MeOH (1.5 mL). After 15 min, the reaction was transferred to a separatory<br />
funnel with Et 2O and washed first with 5% HCl (15 mL) and then with a mixture of sat.<br />
aq NaHCO 3 and brine (1:1, 20 mL). The aqueous layers were extracted with Et 2O<br />
(2 ” 40 mL), and the combined organics were dried (MgSO 4). Filtration through a short silica<br />
gel plug with additional Et 2O, and concentration in vacuo provided the crude, fully protected<br />
lactone which was purified by chromatography (silica gel, Et 2O/hexanes 1:3) to afford<br />
73 as a pale yellow oil; yield: 187 mg (99%).<br />
Cleavage<br />
FOR PERSONAL USE ONLY<br />
4.4.17 <strong>Silyl</strong> <strong>Ethers</strong> 397<br />
4.4.17.4.2 Method 2:<br />
Cleavage ofTriisopropylsilyl <strong>Ethers</strong> with<br />
Tetrabutylammonium Fluoride<br />
The most general method for cleavage of a triisopropylsilyl ether is with tetrabutylammonium<br />
fluoride, however, this reagent typically exhibits no selectivity between silyl ethers<br />
of this class that are situated in different structural environments. Nevertheless, it is possible<br />
to retain a triisopropylsilyl ether while a more susceptible silyl ether, including a<br />
secondary tert-butyldiphenylsilyl ether, is cleaved with this reagent (see Scheme 48, Section<br />
4.4.17.5.4). The conventional protocol for removing a triisopropylsilyl ether is illus-<br />
H<br />
O<br />
73<br />
O<br />
O<br />
O<br />
O<br />
for references see p 410<br />
White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg <strong>Thieme</strong> Verlag KG
trated in the conversion of 74 into diol 75 (Scheme 37), a late intermediate in a synthesis<br />
of milbemycin D. [65]<br />
Scheme 37 Cleavage of a Triisopropylsilyl Ether with Tetrabutylammonium Fluoride [65]<br />
TIPSO<br />
O<br />
OH<br />
O<br />
FOR PERSONAL USE ONLY<br />
398 Science of Synthesis 4.4 Silicon Compounds<br />
74<br />
O<br />
O<br />
O<br />
Pr i<br />
HO<br />
O<br />
TBAF<br />
THF, rt<br />
95%<br />
(4S,6R,25R)-25-Isopropyl-5-O-demethyl-28-deoxy-3,4-dihydro-6,28-epoxymilbemycin B<br />
(75): [65]<br />
1 M TBAF in THF (0.23 mL, 0.23 mmol) was added to a soln of macrolactone 74 (0.054 g,<br />
0.075 mmol) in THF (1.0 mL). The resulting soln was stirred overnight at rt, concentrated<br />
in vacuo, and purified by column chromatography (silica gel, 10±50% EtOAc/hexanes) to<br />
afford diol 75 as a white foam; yield: 0.040 g (95%).<br />
4.4.17.4.3 Method 3:<br />
Cleavage ofTriisopropylsilyl <strong>Ethers</strong> with Tris(dimethylamino)sulfur<br />
(Trimethylsilyl)difluoride<br />
Tris(dimethylamino)sulfur (trimethylsilyl)difluoride (TASF) as a source of fluoride ion has<br />
been used to cleave triisopropylsilyl ethers in situations where the basicity of tetrabutylammonium<br />
fluoride would be destructive toward other functionality. An example in<br />
which only tris(dimethylamino)sulfur (trimethylsilyl)difluoride could be employed to<br />
successfully cleave a triisopropylsilyl ether is seen in the conversion of 76 into baccatin<br />
III (78, Scheme 38). [81] Cleavage of the silyl ether to yield alcohol 77 was followed by treatment<br />
with phenyllithium, which removed the 2,2,2-trichloroethoxycarbonyl (Troc) protection<br />
and opened the cyclic carbonate en route to triol 78 (accompanied by a 46% yield<br />
of 10-O-deacetylbaccatin III).<br />
White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg <strong>Thieme</strong> Verlag KG<br />
OH<br />
O<br />
75<br />
O<br />
O<br />
O<br />
Pr i
Scheme 38 Cleavage of a Triisopropylsilyl Ether with Tris(dimethylamino)sulfur (Trimethylsilyl)difluoride<br />
[81]<br />
AcO O OTroc<br />
TIPSO H<br />
O O OAc<br />
O<br />
76<br />
FOR PERSONAL USE ONLY<br />
4.4.17 <strong>Silyl</strong> <strong>Ethers</strong> 399<br />
O<br />
TASF, THF, 0 oC, 5 min<br />
96%<br />
PhLi, THF<br />
33%<br />
AcO O OTroc<br />
HO H<br />
O O OAc<br />
O<br />
77<br />
O<br />
AcO O OH<br />
10<br />
HO H O<br />
HO BzO<br />
78<br />
OAc<br />
[3aS-(3aá,5â,8á,9aá,10á,11aâ,13aâ,13bâ,13cá)]-8,13a-Diacetoxy-5-hydroxy-3a,7-methano-6,9a,14,14-tetramethyl-2,9-dioxo-4,5,8,9,9a,10,11,11a,13,13a,13b,13c-dodecahydro-<br />
3aH-oxeto[2¢¢,3¢¢:5¢,6¢]benzo[1¢,2¢:3,4]cyclodeca[1,2-d]-1,3-dioxol-10-yl 2,2,2-Trichloroethyl<br />
Carbonate (77): [81]<br />
To silyl ether 76 (3.2 mg, 4 ìmol) in THF (0.8 mL) at 08C was added TASF (4.0 mg, 15 ìmol),<br />
and the mixture was stirred for 5 min at 0 8C. The reaction was quenched by addition of<br />
sat. aq NaHCO 3. The aqueous layer was extracted with Et 2O. The combined organic layers<br />
were washed with H 2O and sat. brine, and then dried (anhyd Na 2SO 4). The crude mixture<br />
was filtered and concentrated under reduced pressure. Purification of the resultant residue<br />
by flash chromatography (silica gel, EtOAc/hexanes 3:7) provided alcohol 77; yield:<br />
2.5 mg (96%).<br />
4.4.17.4.4 Method 4:<br />
Cleavage ofTriisopropylsilyl <strong>Ethers</strong> with<br />
Hydrogen Fluoride±Pyridine Complex<br />
Hydrogen fluoride±pyridine complex, used in a mixed tetrahydrofuran/pyridine solvent<br />
system, affords a convenient method for removing the triisopropylsilyl residue from oxygen.<br />
The final step in a synthesis of the immunosuppressant rapamycin (80) involved unmasking<br />
of both a triisopropylsilyl and a tert-butyldimethylsilyl ether, for which hydrogen<br />
fluoride±pyridine complex treatment of 79 served well (Scheme 39). [82]<br />
for references see p 410<br />
White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg <strong>Thieme</strong> Verlag KG
Scheme 39 Cleavage of a Triisopropylsilyl and a tert-Butyldimethylsilyl Ether with Hydrogen<br />
Fluoride±Pyridine Complex [82]<br />
TIPSO<br />
MeO<br />
O<br />
HO<br />
N<br />
O<br />
O<br />
O<br />
MeO<br />
O<br />
FOR PERSONAL USE ONLY<br />
400 Science of Synthesis 4.4 Silicon Compounds<br />
79<br />
O<br />
TBDMSO<br />
OMe<br />
O<br />
HO<br />
MeO<br />
HF py, py, THF<br />
0 oC to rt, 48 h<br />
69%<br />
O O HO<br />
(±)-Rapamycin (80): [82]<br />
At 0 8C a soln of synthetic hemiketal (±)-79 (5.1 mg, 4.3 ìmol) in THF (0.5 mL) was treated<br />
with pyridine (0.5 mL) followed by HF·pyridine (0.5 mL). The mixture was warmed to rt,<br />
stirred for 48 h, and then partitioned between Et 2O (10 mL) and H 2O (10 mL). The organic<br />
phase was washed with sat. aq CuSO 4 (5 mL), sat. aq NaHCO 3 (5 mL), H 2O (5 mL), and brine<br />
(5 mL), dried (MgSO 4), filtered, and concentrated. Flash chromatography (hexanes/EtOAc<br />
1:1 then 1:3) provided synthetic rapamycin (80) as a clear oil; yield: 2.7 mg (69%). Recrystallization<br />
(acetone/hexanes 4:6) gave (±)-80 as a white solid.<br />
(−)-80<br />
4.4.17.4.5 Method 5:<br />
Cleavage ofTriisopropylsilyl <strong>Ethers</strong> under Acidic Conditions<br />
Although acidic conditions are not often used to cleave triisopropylsilyl ethers, available<br />
evidence suggests that silyl ethers of this class are quite susceptible to cleavage in the<br />
presence of acidic reagents. [76,83] Thus, the triisopropylsilyl blocking group was removed<br />
from the mycotrienin precursor 81 with 4-toluenesulfonic acid in methanol to yield alcohol<br />
82 without affecting the adjacent tert-butyldimethylsilyl ether (Scheme 40). [84] The<br />
sensitive triene unit of 81 was also stable under these conditions.<br />
White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg <strong>Thieme</strong> Verlag KG<br />
OMe<br />
O
Scheme 40 Selective Cleavage of a Triisopropylsilyl Ether under Acidic Conditions [84]<br />
TBDMSO<br />
TIPSO<br />
81<br />
OMe<br />
OMe O<br />
NH<br />
OMe<br />
TsOH, MeOH, rt, 30 min<br />
90%<br />
TBDMSO<br />
HO<br />
82<br />
OMe<br />
OMe O<br />
(5R,6E,8E,10E,13S,14S,15S,16Z)-15-(tert-Butyldimethylsiloxy)-13-hydroxy-5,22,24-trimethoxy-14,16-dimethyl-2-azabicyclo[18.3.1]tetracosa-1(24),6,8,10,16,20,22-heptaen-3-one<br />
(82): [84]<br />
A soln of triene 81 (50 mg, 0.066 mmol) in MeOH (6.0 mL) was treated with catalytic TsOH<br />
(3.0 mg, 0.017 mmol, 0.25 equiv). The mixture was stirred at rt for 30 min and subsequently<br />
diluted with NaHCO 3 and H 2O (20 mL). The mixture was extracted with EtOAc<br />
(3 ” 25 mL), dried (MgSO 4), and concentrated in vacuo. Purification on silica gel (20 to<br />
30% EtOAc/petroleum ether) afforded alcohol 82 as a colorless oil; yield: 36 mg (90%).<br />
4.4.17.5 tert-Butyldiphenylsilyl <strong>Ethers</strong><br />
The tert-butyldiphenylsilyl (TBDPS) ether as a masking device for alcohols was introduced<br />
by Hanessian in order to provide a protecting group more stable toward acidic reagents<br />
than other silyl ethers. [85] tert-Butyldiphenylsilyl ethers are inert under acidic conditions<br />
which can cleave tert-butyldimethylsilyl ethers, and they typically survive those acidic reagents<br />
used to cleave alkyl ethers such as trityl and tetrahydropyranyl. The diminished<br />
reactivity of tert-butyldiphenylsilyl ethers toward electrophiles is thought to be due to<br />
the electron-withdrawing effect of the phenyl substituents attached to silicon. However,<br />
the tert-butyldiphenylsilyl group is more easily cleaved than the tert-butyldimethylsilyl<br />
group with sodium hydroxide. [86]<br />
Formation<br />
FOR PERSONAL USE ONLY<br />
4.4.17 <strong>Silyl</strong> <strong>Ethers</strong> 401<br />
4.4.17.5.1 Method 1:<br />
<strong>Silyl</strong>ation ofAlcohols with tert-Butyldiphenylsilyl Chloride<br />
Both primary and secondary alcohols can be converted into their tert-butyldiphenylsilyl<br />
ethers, the usual reagent for this being the chlorosilane (tert-butyldiphenylsilyl chloride,<br />
TBDPSCl). Secondary alcohols, if sterically hindered, may require elevated reaction temperatures<br />
for efficient silylation with this reagent, as seen in the protection of ethyl (2S)-2hydroxy-3-methylbutanoate<br />
(83) as its tert-butyldiphenylsilyl ether 84 (Scheme 41). [85]<br />
NH<br />
OMe<br />
for references see p 410<br />
White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg <strong>Thieme</strong> Verlag KG
Scheme 41 <strong>Silyl</strong>ation of a Secondary Alcohol with tert-Butyldiphenylsilyl Chloride [87]<br />
OH<br />
83<br />
CO 2Et<br />
TBDPSCl, imidazole<br />
DMF, 80 oC, 7 h<br />
92%<br />
CO 2Et<br />
OTBDPS<br />
84<br />
Ethyl (2S)-2-(tert-Butyldiphenylsiloxy)-3-methylbutanoate (84): [87]<br />
To a soln of ethyl (2S)-2-hydroxy-3-methylbutanoate (83; 2.22 g, 15.2 mmol) in DMF<br />
(20 mL) were added imidazole (1.24 g, 18.2 mmol) and TBDPSCl (5.00 g, 18.2 mmol) and<br />
the mixture was stirred at 808C. After being stirred for 7 h, the mixture was diluted with<br />
H 2O (60 mL) and extracted with CH 2Cl 2 (3 ” 60 mL). The combined extracts were washed<br />
with brine, dried (MgSO 4), and concentrated in vacuo. Column chromatography (silica<br />
gel, hexane) gave silyl ether 84 as a colorless oil; yield: 5.40 g (92%).<br />
4.4.17.5.1.1 Variation 1:<br />
In the Presence of4-(Dimethylamino)pyridine<br />
<strong>Silyl</strong>ation with tert-butyldiphenylsilyl chloride can be carried out at room temperature if<br />
4-(dimethylamino)pyridine is included in the reaction mixture, [88] as seen in the quantitative<br />
conversion of the hydroxyspiroketal 85 into its silyl ether 86 (Scheme 42). [65]<br />
Scheme 42 <strong>Silyl</strong>ation with tert-Butyldiphenylsilyl Chloride in the Presence of<br />
4-(Dimethylamino)pyridine [65]<br />
HO<br />
O<br />
85<br />
O Pr i<br />
TBDPSCl, DMAP<br />
imidazole, DMF, 25 oC, 60 h<br />
100%<br />
TBDPSO<br />
O<br />
86<br />
O Pr i<br />
(2R,3S,8S,10S)-10-(tert-Butyldiphenylsiloxy)-2-isopropyl-3-methyl-8-vinyl-1,7dioxaspiro[5.5]undecane<br />
(86): [65]<br />
To a soln of alcohol 85 (4.470 g, 17.6 mmol), imidazole (2.64 g, 38.7 mmol) and DMAP<br />
(220 mg, 1.8 mmol) in dry DMF (300 mL) at 25 8C was added TBDPSCl (4.83 g, 17.6 mmol),<br />
and the mixture was stirred for 60 h. To this soln was added pentane (500 mL) and H 2O<br />
(300 mL). The aqueous phase was extracted with pentane (2 ” 100 mL), and the organic extracts<br />
were combined and dried (Na 2SO 4). The extracts were concentrated and the residue<br />
was purified by flash chromatography to give silyl ether 86 as a clear viscous oil; yield:<br />
8.67 g (100%).<br />
4.4.17.5.1.2 Variation 2:<br />
Using Butyllithium<br />
FOR PERSONAL USE ONLY<br />
402 Science of Synthesis 4.4 Silicon Compounds<br />
The reaction of butane-1,4-diol (87) with tert-butyldiphenylsilyl chloride at ±788C using<br />
butyllithium as a base gives the monosilylation product 88 in high yield (Scheme 43). [89]<br />
This useful method of desymmetrizing a diol is undoubtedly assisted by the large steric<br />
bulk of the tert-butyldiphenylsilyl group.<br />
White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg <strong>Thieme</strong> Verlag KG
Scheme 43 Monosilylation of Butane-1,4-diol with tert-Butyldiphenylsilyl Chloride and<br />
Butyllithium [89]<br />
HO<br />
87<br />
OH<br />
TBDPSCl (0.33 equiv), BuLi (0.33 equiv)<br />
THF, −78 oC to rt<br />
90%<br />
HO<br />
88<br />
OTBDPS<br />
4-(tert-Butyldiphenylsiloxy)butan-1-ol (88): [89]<br />
A soln of butane-1,4-diol (6.0 g, 66.6 mmol) in THF (35 mL) was cooled to ±788C under N 2,<br />
and the resulting white suspension was treated in dropwise fashion, with vigorous stirring,<br />
with 2.5 M BuLi in hexanes (8.9 mL, 22.2 mmol, 0.33 equiv). The mixture became<br />
very viscous. After being stirred for an additional 5 min, the mixture was treated in dropwise<br />
fashion with TBDPSCl (5.76 mL, 22.2 mmol, 0.33 equiv), and the resulting mixture<br />
was allowed to warm to rt, which gave a white suspension. After being stirred at rt for<br />
40 min, the mixture was treated with H 2O (35 mL) and sat. aq NH 4Cl (35 mL), and the separated<br />
aqueous layer was extracted with Et 2O (3 ” 50 mL). The combined organic extracts<br />
were dried (MgSO 4), filtered, concentrated under reduced pressure, and chromatographed<br />
(hexanes/EtOAc 100:15) to give 88 as a colorless oil; yield: 6.58 g (90%).<br />
4.4.17.5.2 Method 2:<br />
<strong>Silyl</strong>ation ofAlcohols with tert-Butyldiphenylsilyl<br />
Trifluoromethanesulfonate<br />
The more reactive tert-butyldiphenylsilyl trifluoromethanesulfonate (TBDPSOTf) is used<br />
to silylate hindered alcohols that will not react with tert-butyldiphenylsilyl chloride. An<br />
example is silylation of the breynolide intermediate 89 to give ether 90 (Scheme 44). [90]<br />
As with other silyl triflates, this reagent is commonly used with 2,6-lutidine in dichloromethane.<br />
Scheme 44 <strong>Silyl</strong>ation with tert-Butyldiphenylsilyl Trifluoromethanesulfonate [90]<br />
CO2Me<br />
H<br />
HO OMEM<br />
H<br />
S<br />
89<br />
FOR PERSONAL USE ONLY<br />
4.4.17 <strong>Silyl</strong> <strong>Ethers</strong> 403<br />
TBDPSOTf, 2,6-lut<br />
CH2Cl2, 0 oC to rt<br />
94%<br />
TBDPSO<br />
H<br />
90<br />
S<br />
CO 2Me<br />
H OMEM<br />
Methyl (3R,3aR,6S,7S,7aS)-3-(tert-Butyldiphenylsiloxy)-7-[(2-methoxyethoxy)methoxy]octahydrobenzo[b]thiophene-6-carboxylate<br />
(90): [90]<br />
A soln of alcohol 89 (1.01 g, 3.16 mmol) in CH 2Cl 2 (25 mL) was cooled to 08C and treated<br />
with 2,6-lutidine (3.65 mL, 31.6 mmol) and TBDPSOTf (2.45 g, 6.32 mmol). The mixture<br />
was stirred at 08C for 30 min and at rt for 2 h, and then was quenched with sat. NaHCO 3<br />
soln. After the addition of CH 2Cl 2 (100 mL), the pH of the aqueous phase was adjusted to<br />
ca. 7.0 with 1 M HCl. The aqueous phase was extracted with CH 2Cl 2 (3 ” 150 mL), and the<br />
combined organic phases were dried (K 2CO 3), filtered, and concentrated in vacuo. Flash<br />
chromatography (EtOAc/hexanes 2:8) afforded silyl ether 90 as a clear, colorless oil; yield:<br />
1.66 g (94%).<br />
4.4.17.5.3 Method 3:<br />
Migration ofa tert-Butyldiphenylsilyl Group to an Alcohol<br />
Although the tert-butyldiphenylsilyl group is considered to be less prone to migration<br />
than the tert-butyldimethylsilyl group (Section 4.4.17.3.3) [91] and other silyl derivatives, it<br />
can migrate to a hydroxy substituent under basic conditions. Migration of this silyl group<br />
for references see p 410<br />
White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg <strong>Thieme</strong> Verlag KG
can occur from a carbon atom or from oxygen. Thus, while it is usually very difficult to<br />
silylate a tertiary alcohol with tert-butyldiphenylsilyl chloride or trifluoromethanesulfonate,<br />
intramolecular rearrangement of a hydroxylated tert-butyldiphenylsilane can provide<br />
a means of accomplishing this protection. An example of tert-butyldiphenylsilyl migration<br />
is seen in the rearrangement of hydroxylated silane 91 to silyl ether 92 mediated<br />
by 1,8-diazabicyclo[5.4.0]undec-7-ene as the base (Scheme 45). [92]<br />
Scheme 45 Rearrangement of a Hydroxylated tert-Butyldiphenylsilane<br />
to a tert-Butyldiphenylsilyl Ether [92]<br />
TBDPS<br />
O OAc<br />
OH<br />
91<br />
OAc<br />
DBU, CH2Cl2<br />
rt, 6 h<br />
90%<br />
O OAc<br />
OAc<br />
OTBDPS<br />
92<br />
The severe steric crowding that attends a tertiary tert-butyldiphenylsilyl ether such as 92<br />
may prompt migration of the silyl residue to a less congested site, if one is available. For<br />
example, exposure of 93 to sodium hydroxide is sufficient to cause an internal rearrangement<br />
of the tertiary silyl ether to yield the secondary tert-butyldiphenylsilyl ether 94<br />
(Scheme 46); [92] the primary tert-butyldimethylsilyl ether remained unaffected under<br />
these reaction conditions.<br />
Scheme 46 Rearrangement of a Tertiary tert-Butyldiphenylsilyl Ether to<br />
a Secondary tert-Butyldiphenylsilyl Ether [92]<br />
O<br />
OH OAc<br />
OTBDPS<br />
93<br />
OTBDMS<br />
NaOH, t-BuOH<br />
H2O, rt, 3 h<br />
70%<br />
TBDPSO OAc<br />
O<br />
OH<br />
94<br />
OTBDMS<br />
(4S,5R)-5,6-Diacetoxy-4-(tert-butyldiphenylsiloxy)-4-methylhex-1-en-3-one (92): [92]<br />
To a soln of enone 91 (150 mg, 0.31 mmol) in CH 2Cl 2 (0.5 mL) at rt was added DBU (10 mg).<br />
The mixture was stirred for 6 h and then quenched with aq NH 4Cl and extracted with<br />
Et 2O. The ethereal layer was washed with brine and dried (MgSO 4). After removal of solvent<br />
under reduced pressure, the residue was chromatographed (silica gel, Et 2O/hexanes<br />
1:10) to afford enone 92 as a clear oil; yield: 135 mg (90%).<br />
(2R,3S,4S,5R)-2-Acetoxy-1-(tert-butyldimethylsiloxy)-4-(tert-butyldiphenylsiloxy)-5,6epoxy-3-methylhexan-3-ol<br />
(94): [92]<br />
A soln of epoxide 93 (200 mg, 0.35 mmol) in 1 M NaOH/t-BuOH (1:6, 1.0 mL) was stirred at<br />
rt for 3 h. The mixture was quenched with aq NH 4Cl and extracted with Et 2O. The ethereal<br />
layer was dried (MgSO 4) and concentrated. The residue was chromatographed (silica gel,<br />
Et 2O/hexanes 1:4) to afford tertiary alcohol 94 as a clear oil; yield: 140 mg (70%).<br />
Cleavage<br />
FOR PERSONAL USE ONLY<br />
404 Science of Synthesis 4.4 Silicon Compounds<br />
4.4.17.5.4 Method 4:<br />
Cleavage of tert-Butyldiphenylsilyl <strong>Ethers</strong> with<br />
Tetrabutylammonium Fluoride<br />
In common with other silyl ethers, tert-butyldiphenylsilyl ethers are readily cleaved with<br />
tetrabutylammonium fluoride in tetrahydrofuran. [93] The reagent shows no selectivity for<br />
tert-butyldiphenylsilyl ethers in different structural environments. For example, the final<br />
step in a synthesis of (+)-isobretonin A (96) involves deprotection of both the phenolic and<br />
the secondary tert-butyldiphenylsilyl ether of 95 with tetrabutylammonium fluoride<br />
(Scheme 47). [94]<br />
White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg <strong>Thieme</strong> Verlag KG
Scheme 47 Cleavage of a Bis(tert-butyldiphenylsilyl ether) with Tetrabutylammonium<br />
Fluoride [94]<br />
TBDPSO<br />
O<br />
OTBDPS<br />
O O<br />
95<br />
HO<br />
3<br />
O<br />
OH<br />
O O<br />
96<br />
TBAF, THF<br />
0 oC to rt, 12 h<br />
83%<br />
A tert-butyldiphenylsilyl ether is more susceptible to attack by fluoride ion than a triisopropylsilyl<br />
ether, a property that can be attributed to electron withdrawal by the phenyl<br />
substituents on silicon. This distinction is manifested, for example, in the selective cleavage<br />
of the tert-butyldiphenylsilyl ether of 97, yielding alcohol 98 in which the triisopropylsilyl<br />
ether is left intact (Scheme 48). [65]<br />
Scheme 48 Cleavage of a tert-Butyldiphenylsilyl Ether with Tetrabutylammonium<br />
Fluoride [65]<br />
TIPSO<br />
O<br />
CO2H<br />
FOR PERSONAL USE ONLY<br />
4.4.17 <strong>Silyl</strong> <strong>Ethers</strong> 405<br />
TBDPSO<br />
97<br />
O<br />
O<br />
Pr i<br />
TIPSO<br />
TBAF, THF<br />
rt, 4 d<br />
68%<br />
(+)-Isobretonin A (96): [94]<br />
To a soln of bis(silyl ether) 95 (190 mg, 0.2 mmol) in THF (20 mL) at 08C under argon was<br />
added 1 M TBAF in THF (0.5 mL, 0.5 mmol). The mixture was allowed to reach rt and was<br />
stirred for 12 h. The reaction was then quenched with silica gel (2 g) and the soln was concentrated.<br />
The mixture was dissolved in CH 2Cl 2 (1 mL) and purified by column chromatography<br />
(silica gel, EtOAc/hexane 1:3) to give isobretonin A (96); yield: 68.38 mg (83%).<br />
(3Z,3aR,4R,6S,7S,7aS)-3-{(2E,4R,6E)-8-[(2R,4S,8R,9S)-4-Hydroxy-8-isopropyl-9-methyl-1,7dioxaspiro[5.5]undec-2-yl]-4,6-dimethylocta-2,6-dienylidene}-6-methyl-7-(triisopropylsiloxy)octahydrobenzofuran-4-carboxylic<br />
Acid (98): [65]<br />
1 M TBAF in THF (0.24 mL, 0.24 mmol) was added to a soln of acid 97 (0.24 g, 0.25 mmol) in<br />
THF (5.0 mL). The resulting soln was stirred for 3 d at rt, and more TBAF soln (0.12 mL,<br />
0.12 mmol) was added. Following an additional 1 d of stirring, the soln was concentrated<br />
O<br />
CO 2H<br />
98<br />
HO<br />
O<br />
O<br />
3<br />
Pr i<br />
for references see p 410<br />
White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg <strong>Thieme</strong> Verlag KG
in vacuo and purified by column chromatography (silica gel, 25±50% EtOAc/hexanes, then<br />
10±30% MeOH/hexanes) to provide hydroxy acid 98 as a white foam; yield: 0.123 g (68%).<br />
4.4.17.5.5 Method 5:<br />
Cleavage of tert-Butyldiphenylsilyl <strong>Ethers</strong> with<br />
Tetrabutylammonium Fluoride in Acetic Acid<br />
Acetic acid may be used as a buffer in the cleavage of tert-butyldiphenylsilyl ethers with<br />
tetrabutylammonium fluoride in tetrahydrofuran. [95] This valuable technique moderates<br />
the basicity that accompanies this source of fluoride ion and which can sometimes lead to<br />
destruction of base-sensitive substrates. An application of this method is seen in the final<br />
step of a synthesis of (+)-acutiphycin (100), where a tert-butyldiphenylsilyl ether is<br />
smoothly removed from 99 (Scheme 49). [96] An attempt to unmask this ether with unbuffered<br />
tetrabutylammonium fluoride led to decomposition.<br />
Scheme 49 Cleavage of a tert-Butyldiphenylsilyl Ether with Tetrabutylammonium<br />
Fluoride in the Presence of Acetic Acid [96]<br />
OTBDPS<br />
O<br />
OH H<br />
O O<br />
O<br />
99<br />
FOR PERSONAL USE ONLY<br />
406 Science of Synthesis 4.4 Silicon Compounds<br />
OH<br />
TBAF, AcOH<br />
THF, rt, 42 h<br />
95%<br />
OH<br />
O<br />
OH H<br />
O O<br />
O<br />
(+)-Acutiphycin (100): [96]<br />
A stock soln was prepared by addition of AcOH (0.15 mL) to a soln of 1.0 M TBAF in THF<br />
(2.5 mL). <strong>Silyl</strong> ether (+)-99 (6.0 mg, 8.7 ìmol) was dissolved in THF (3.3 mL) and treated<br />
with a portion of the stock soln (1.5 mL). After 42 h at rt, the mixture was diluted with<br />
EtOAc (25 mL), washed with sat. aq NaHCO 3 (2 ” 15 mL) and brine (15 mL), dried (MgSO 4),<br />
filtered, and concentrated. Flash chromatography (hexane/EtOAc 2:1) afforded (+)-100 as a<br />
colorless, amorphous solid; yield: 3.8 mg (95%).<br />
4.4.17.5.6 Method 6:<br />
Cleavage of tert-Butyldiphenylsilyl <strong>Ethers</strong> with<br />
Tris(dimethylamino)sulfur (Trimethylsilyl)difluoride<br />
The mild fluoride source tris(dimethylamino)sulfur (trimethylsilyl)difluoride (TASF) [59]<br />
can be employed to cleave a tert-butyldiphenylsilyl ether in the presence of certain other<br />
silyl ethers, including a tert-butyldimethylsilyl ether. This valuable selectivity arises from<br />
the increased propensity of a silicon atom to suffer nucleophilic attack when it carries<br />
aryl substituents as compared to alkyl groups. A demonstration of the unique selectivity<br />
of tris(dimethylamino)sulfur (trimethylsilyl)difluoride has been provided in the conversion<br />
of the bis(silyl ether) 101 into alcohol 102 (Scheme 50). [97]<br />
White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg <strong>Thieme</strong> Verlag KG<br />
100<br />
OH
Scheme 50 Selective Cleavage of a tert-Butyldiphenylsilyl Ether with Tris(dimethylamino)sulfur<br />
(Trimethylsilyl)difluoride [97]<br />
TBDMSO<br />
TBDPSO<br />
101<br />
O<br />
O<br />
O<br />
Bu t<br />
TASF (1.2 equiv)<br />
DMF, 0 oC to rt<br />
84%<br />
TBDMSO<br />
(2R,5S,6S,9R)-2-tert-Butyl-6-[(1E,3S)-3-(tert-butyldimethylsiloxy)-2-methylhexa-1,5-dienyl]-<br />
8-(hydroxymethyl)-9-methyl-1,3-dioxaspiro[4.5]dec-7-en-4-one (102): [97]<br />
To a 08C soln of bis(silyl ether) 101 (57 mg, 0.080 mmol) in DMF (0.500 mL) was added<br />
1.30 M TASF in DMF (0.073 mL, 0.095 mmol). The reaction was stirred at 0 8C for 2 h, then<br />
warmed to rt for 2 h. The mixture was diluted with EtOAc and washed with pH 7 buffer.<br />
The aqueous layer was extracted with EtOAc (3 ” 10 mL) and the combined organic layers<br />
were dried (MgSO 4), filtered and concentrated in vacuo. The crude oil was purified by<br />
chromatography (silica gel, Et 2O/hexanes 1:1) to give 102; yield: 32 mg (84%).<br />
4.4.17.5.7 Method 7:<br />
Cleavage of tert-Butyldiphenylsilyl <strong>Ethers</strong> with<br />
Hydrogen Fluoride±Pyridine Complex<br />
Hydrogen fluoride±pyridine complex in tetrahydrofuran [98] and hydrogen fluoride in<br />
aqueous acetonitrile [99] are effective reagents for unmasking a tert-butyldiphenylsilyl<br />
ether. They are relatively unselective but are valuable for cleaving a tert-butyldiphenylsilyl<br />
ether where basic conditions (e.g., see Section 4.4.17.5.5) cannot be employed. An application<br />
of the hydrogen fluoride±pyridine reagent is seen in the deprotection of the tertbutyldiphenylsilyl<br />
ether 103 to give alcohol 104 (Scheme 51), an intermediate in a route<br />
to (+)-acetoxycrenulide. [100]<br />
Scheme 51 Cleavage of a tert-Butyldiphenylsilyl Ether with Hydrogen<br />
Fluoride±Pyridine Complex [100]<br />
TBDPSO<br />
O<br />
O H H<br />
103<br />
FOR PERSONAL USE ONLY<br />
4.4.17 <strong>Silyl</strong> <strong>Ethers</strong> 407<br />
HF py<br />
MeCN, H2O, 6 h<br />
85%<br />
HO<br />
O<br />
104<br />
102<br />
O<br />
HO<br />
O H H<br />
H OAc<br />
H OAc<br />
(4S,5R,7R,7aS,8aS)-5-Acetoxy-4-[(1R)-4-hydroxy-1-methylbutyl]-7-methyl-3,4,5,6,7,7a,8,8aoctahydro-1H-cyclopropa[3,4]cycloocta[1,2-c]furan-1-one<br />
(104): [100]<br />
A soln of silyl ether 103 (153 mg, 0.27 mmol) in MeCN (8 mL) was treated with HF·py soln<br />
[prepared by adding 48% HF (1 mL) to a mixture of MeCN (1 mL) and pyridine (2.4 mL) at<br />
08C]in three equal aliquots (0.33 mL each) over 6 h. The mixture was then diluted with<br />
H 2O and extracted with EtOAc. The combined organic extracts were washed with 5%<br />
HCl, sat. NaHCO 3 soln, and brine prior to drying and solvent evaporation. Chromatography<br />
of the residual gel (EtOAc/hexanes 9:1) afforded alcohol 104 as a colorless oil; yield:<br />
77 mg (85%).<br />
O<br />
O<br />
Bu t<br />
for references see p 410<br />
White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg <strong>Thieme</strong> Verlag KG
4.4.17.5.7.1 Variation 1:<br />
Cleavage with Hydrogen Fluoride±Triethylamine Complex<br />
The use of triethylamine in place of pyridine with hydrogen fluoride renders the fluoride<br />
ion a potent nucleophile while suppressing side reactions that occasionally result from<br />
acid catalysis by hydrogen fluoride±pyridine complex. The hydrogen fluoride±triethylamine<br />
system in acetonitrile as the solvent is particularly useful for cleaving tert-butyldiphenylsilyl<br />
ethers in structures that contain acid-sensitive functional groups. The deprotection<br />
of tert-butyldiphenylsilyl ether 105, which bears numerous appendages that<br />
would be susceptible to acidic hydrolysis, illustrates an application of this reagent<br />
(Scheme 52). The resultant primary alcohol 106 was a key intermediate in a synthesis of<br />
(+)-damavaricin D. [101]<br />
Scheme 52 Cleavage of a tert-Butyldiphenylsilyl Ether with Hydrogen Fluoride±Triethylamine<br />
Complex [101]<br />
MOMO<br />
O<br />
OMOM<br />
O<br />
OMOM<br />
FOR PERSONAL USE ONLY<br />
408 Science of Synthesis 4.4 Silicon Compounds<br />
O<br />
SiMe 3<br />
O OAc OAc O O OTBDPS<br />
O O<br />
105<br />
MOMO<br />
O<br />
Et3N HF, MeCN, reflux, 12 h<br />
89%<br />
OMOM<br />
O<br />
OMOM<br />
O<br />
SiMe3<br />
O OAc OAc O O OH<br />
106<br />
O O<br />
2-(Trimethylsilyl)ethyl 8-Allyloxy-5-[(2E,4S,5S,6R,7R,8R,9R,10R,11R,12R)-5,7-diacetoxy-8-<br />
(allylcarbonyloxy)-13-hydroxy-9,11-(isopropylidenedioxy)-2,4,6,10,12-pentamethyl-1-oxotridec-2-enyl]-1,4,6-tris(methoxymethoxy)-3,7-dimethylnaphthalene-2-carboxylate<br />
(106): [101]<br />
A soln of silyl ether 105 (0.70 g, 0.53 mmol) and Et 3N·HF (250 mg, 2.1 mmol) in MeCN<br />
(6.0 mL) was heated at reflux for 12 h. The soln was allowed to cool to 238C then partitioned<br />
between Et 2O (400 mL) and H 2O (150 mL). The organic phase was washed with<br />
NaHCO 3 soln (50 mL) and H 2O (50 mL), dried (MgSO 4), filtered, and concentrated, which<br />
afforded a yellow oil. Purification of the crude product by flash chromatography<br />
(EtOAc/hexanes 3:7) gave the alcohol 106 as a ca. 1:1 mixture of atropisomers (white<br />
foam); yield: 0.51 g (89%).<br />
White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg <strong>Thieme</strong> Verlag KG
4.4.17.6 Other <strong>Silyl</strong> <strong>Ethers</strong><br />
FOR PERSONAL USE ONLY<br />
4.4.17 <strong>Silyl</strong> <strong>Ethers</strong> 409<br />
The need for selectivity in the protection of alcohols has brought forth a suite of silylating<br />
agents bearing a variety of substituents at the silicon atom that extend beyond the structural<br />
types described in Sections 4.4.17.1±4.4.17.5. <strong>Silyl</strong> ethers prepared with these reagents<br />
possess reactivity toward cleavage which varies widely and which can be ªtunedº<br />
to particular applications. The combination of steric and electronic effects of substituents<br />
at silicon in these silyl ethers leads to properties that are often difficult to predict, and<br />
most of the information about silyl ethers in this group has been obtained from empirical<br />
observation.<br />
Although ethers in this group have been less extensively exploited in synthesis than<br />
the silyl ethers described in the foregoing sections, specific examples suggest that they<br />
can play a valuable role in the differential protection of alcohols during a complex synthesis,<br />
and may find more general application as their reactivity becomes better understood.<br />
All of the silyl ethers in this group can be prepared by one or more of the methods described<br />
for silyl ethers in Sections 4.4.17.1±4.4.17.5, the most frequently used method being<br />
reaction of an alcohol with either the silyl chloride, bromide or triflate. The subtle but<br />
real variation in the behavior of these silyl ethers towards cleavage reagents forms the basis<br />
for their utility as specific protection devices for alcohols.<br />
Thus, diethylisopropylsilyl ethers are more stable than triethylsilyl ethers, but are<br />
more easily cleaved than tert-butyldimethylsilyl ethers. Conditions have been described<br />
that result in retention of a secondary tert-butyldimethylsilyl ether while removing a diethylisopropylsilyl<br />
ether. [101] As an operational principle, a diethylisopropylsilyl ether is<br />
considered to be approximately 90 times more stable than a trimethylsilyl ether towards<br />
acidic hydrolysis and 600 times more resistant than a trimethylsilyl ether towards cleavage<br />
with fluoride ion.<br />
An isopropyldimethylsilyl ether [102] is even more labile towards acidic hydrolysis<br />
than a diethylisopropylsilyl ether, and is cleaved rapidly in aqueous acetic acid at room<br />
temperature. [103] Other hydroxy protecting groups, such as a tetrahydropyranyl ether,<br />
will survive conditions that typically cleave an isopropyldimethylsilyl ether.<br />
Triphenylsilyl ethers are usually prepared from the corresponding silyl chloride, [104]<br />
and are quite labile towards basic hydrolysis. They are approximately 400 times less reactive<br />
towards acidic cleavage than trimethylsilyl ethers.<br />
Methyldiphenylsilyl ethers [105] are intermediate in stability between trimethylsilyl<br />
and triethylsilyl ethers. Unlike most trimethylsilyl ethers, they will survive chromatography<br />
on silica gel, but a serious limitation is that they do not withstand many of the common<br />
reagents used in synthesis, including acids, bases, reducing agents, and oxidants.<br />
tert-Butylmethoxyphenylsilyl ethers provide protection for alcohols where selectivity<br />
is desired in the presence of other silyl ethers, especially tert-butyldimethylsilyl or tertbutyldiphenylsilyl<br />
ethers. [106] The tert-butylmethoxyphenylsilyl ether is appreciably more<br />
stable towards acidic hydrolysis than a tert-butyldimethylsilyl ether. On the other hand, a<br />
tert-butylmethoxyphenylsilyl ether is cleaved more readily with fluoride than either a<br />
tert-butyldimethylsilyl or a tert-butyldiphenylsilyl ether, allowing for removal of the former<br />
in the presence of the latter two classes of ethers. [107] Primary, secondary, and tertiary<br />
alcohols can be converted quite readily into their tert-butylmethoxyphenylsilyl ethers,<br />
but the fact that the silicon atom in this class of ethers is stereogenic will result in diastereomers<br />
if the parent alcohol is chiral.<br />
Tris(trimethylsilyl)silyl (sisyl) ethers are among the most stable of the silyl ethers. [108]<br />
Readily prepared by reaction of an alcohol with tris(trimethylsilyl)silyl chloride in the<br />
presence of 4-(dimethylamino)pyridine, these ethers withstand strongly acidic conditions<br />
that will cleave most other silyl ethers. Tris(trimethylsilyl)silyl ethers are cleaved with tetrabutylammonium<br />
fluoride, however, and they can be cleanly removed by photolysis in<br />
methanol.<br />
for references see p 410<br />
White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg <strong>Thieme</strong> Verlag KG
tert-Butoxydiphenylsilyl ethers possess stability towards acidic hydrolysis that is<br />
comparable to that of tert-butylmethoxyphenylsilyl ethers. [109] Like the latter group, they<br />
are also quite labile towards fluoride. An advantage of the tert-butoxydiphenylsilyl group<br />
over the tert-butylmethoxyphenylsilyl residue is that it is achiral and, hence, does not produce<br />
diastereomeric silyl ethers.<br />
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