Sily L Protecting Groups

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4.4.17
FOR PERSONAL USE ONLY
Product Subclass 17: Silyl Ethers
J. D. White and R. G. Carter
General Introduction
A useful feature of silyl ethers is that they greatly increase the volatility of an otherwise nonvolatile polyol. A highly polar and intractable oligosaccharide, for example, can be rendered amenable to gas chromatography and mass spectrometry through exhaustive silylation of its free hydroxy groups. However, the most frequent use made of silyl ethers is for the protection of alcohols.[1,2] Virtually any primary, secondary, or tertiary alcohol can be converted into a silyl ether, and there is usually the option of differential protection of polyhydroxylic structures with an appropriate choice of silylating agent.[3] By far the most general method for preparation of a silyl ether is through the reaction of an alcohol with a silylating agent that bears a leaving group. Chlorosilanes and silyl triflates are the most common reagents for this purpose, and are typically used in the presence of a base. The nature of this base can significantly affect the reactivity of the silylating agent. The ability to modulate the reactivity of the silylating agent through variation of the substituents on silicon contributes much versatility to the synthesis of silyl ethers. It is also an important factor in the selective cleavage of silyl ethers (deprotection). Both steric and electronic properties of the substituents at silicon play a role in the formation of silyl ethers and are especially important when considering the stability of a silyl ether toward acids and bases. For some of the most commonly used silyl ethers, the stability toward acid increases in the order trimethylsilyl (TMS, 1) < triethylsilyl (TES, 64) < tert-butyldimethylsilyl (TBDMS, 2 104) < triisopropylsilyl (TIPS, 7 105) < tert-butyldiphenylsilyl (TBDPS, 5 106), while the stability towards base increases in the order TMS (1) < TES (~102) < TBDMS ~ TBDPS (2 104) < TIPS (105). This wide range of stability exhibited by silyl ethers makes their selective cleavage a relatively straightforward matter with the appropriate reagent. Fluoride in the form of tetrabutylammonium fluoride, pyridinium fluoride or a hydrogen fluoride/acetonitrile solution is a particularly effective reagent for cleavage of silyl ethers, the Si-F bond being 30 kcal mol1 stronger than a Si-O bond. A review that discusses selective cleavage of silyl ethers is available.[4] There is considerable debate as to whether silyl ethers are more[5] or less[6] basic than alkyl ethers, but it is generally agreed that the oxygen atom of a silyl ether is less strongly coordinating, for example with Lewis acids, than the oxygen of an alkyl ether.[7] As a consequence, silyl ethers generally chelate poorly with metal cations and do not perform well as directing elements in processes where stereocontrol is paramount. This, of course, can be an advantage when coordination is to be avoided, such as when chelation control would give the stereoisomer that is not required. However, there is evidence to suggest that in certain situations silyl ethers can complex with a metal cation.[8] It is important to remember that a characteristic of silyl ethers is that the silyl group can migrate to an adjacent hydroxy function when base is present.[9] The reaction is thought to proceed through a hypervalent, pentacoordinate silicon intermediate.[10] The direction of migration is almost always toward the less highly substituted or less crowded hydroxy group. Thus, although the Si-O bond (1.64 ) is appreciably longer than a C-O bond (1.43 ), the siloxy group is nevertheless sensitive to the steric environment at the carbon to which the silyl ether is attached. Silyl migration between oxygens is particularfor references see p 410
White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg Thieme Verlag KG
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Science of Synthesis 4.4 Silicon Compounds
ly common with tert-butyldimethylsilyl ethers,[9] but less so with triisopropylsilyl and tertbutyldiphenylsilyl ethers. Silyl migration of this type is most frequently seen where oxygens bear a 1,2-relationship[10] or a 1,3-relationship,[11] although more distant migrations are known. This aspect of silyl ether chemistry has sometimes presented problems in complex syntheses where a specific hydroxy protection is desired. It can pose severe difficulties for researchers in the fields of carbohydrate[12] and ribooligonucleotide[13] synthesis where unwanted silyl migrations often occur quite readily. Silyl migration between carbon and oxygen has long been recognized as an important feature of silicon chemistry; in fact, the rearrangement can be used as a preparative method for silyl ethers.[14] The transfer of a silyl group from carbon to oxygen was first described in the context of a [1,2] shift by Brook,[15] for whom the rearrangement is named. It was subsequently found that migration can occur between nonadjacent atoms, leading to [1,n]-Brook rearrangements where n 5.[16] It has been shown that silicon retains its configuration in the course of a Brook rearrangement.[17] The rearrangement requires the presence of a strong base and is synthetically most useful when the carbanion resulting from silyl migration is stabilized.[18] The reverse migration of silyl groups from oxygen to carbon (retro-Brook rearrangement) was discovered by West, initially as a [1,3] shift[19] and later as a [1,2] migration.[20] Longer range retro-Brook rearrangements have also been noted.[21] These reactions take place when silyl ethers are exposed to a strong base, such as an alkyllithium, which may be used to effect halogenmetal or metalmetal exchange. Silyl migration to the resultant carbanion is driven by the formation of a more stable alkoxide species.
4.4.17.1
Trimethylsilyl Ethers
As the least stable of the family of silyl ethers, trimethylsilyl (TMS) ethers have found only limited utility as protecting groups in complex synthesis. Their sensitivity toward mild acids (e.g., acetic acid) and bases (potassium carbonate in methanol) makes their survival through multistep operations in a synthetic sequence problematic. Even chromatography on silica gel can suffice to cleave a trimethylsilyl ether. The most frequent use made of trimethylsilyl ethers is to mask polar functional groups, primarily hydroxy and carboxy groups, for the purpose of increasing the volatility of an otherwise nonvolatile compound. Since trimethylsilyl ethers are thermally quite stable, the resultant (poly)silyl ether can be subjected to gas chromatography and mass spectrometry without fear of decomposition. This technique has been widely applied in the carbohydrate area where exhaustive silylation, for example with N-(trimethylsilyl)acetamide, leads to a persilylated sugar.[22]
Formation
4.4.17.1.1
Method 1: Silylation of Alcohols with Chlorotrimethylsilane
A variety of silylating agents is available for the preparation of trimethylsilyl ethers, but chlorotrimethylsilane (TMSCl) is perhaps the most frequently employed. It is used in the presence of a base, typically imidazole or triethylamine, which removes hydrogen chloride formed during the silylation. There is very little difference in the rate of silylation of primary, secondary, and tertiary alcohols with this reagent, and selectivity in protection of alcohols is not usually possible. A typical silylation with chlorotrimethylsilane is that of alcohol 1 to give silyl ether 2 (Scheme 1); it is noteworthy that the terminal alkyne of 1 does not undergo silylation under these conditions.[23]
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373
Scheme 1 Silylation with Chlorotrimethylsilane[23]

TMSCl, imidazole CH2Cl2, rt, 10 h 95%
OPMB
OPMB
OH 1
OTMS 2
TMSCl (747 L, 5.92 mmol) followed by imidazole (619 mg, 9.10 mmol) were added to a stirred soln of alcohol 1 (1.129 g, 4.55 mmol) in CH2Cl2 (50 mL) at rt under N2. A white precipitate formed immediately. The mixture was stirred for 10 h and was then diluted with EtOAc (100 mL). The organic phase, after washing with H2O (15 mL) and sat. aq NaCl (15 mL), was dried (Na2SO4), filtered, and concentrated. Column chromatography (silica gel, hexanes/EtOAc 7:1) of the residue gave 2 as a clear, colorless oil; yield: 1.384 g (95%).
4.4.17.1.2
(4S,5R)-6-(4-Methoxybenzyloxy)-5-methyl-4-(trimethylsiloxy)hex-1-yne (2):[23]
Method 2: Silylation of Alcohols with Trimethylsilyl Trifluoromethanesulfonate
Trimethylsilyl trifluoromethanesulfonate (trimethylsilyl triflate, TMSOTf), a powerful silylating agent,[24] has gained popularity among synthetic chemists since it became readily available from commercial sources. Despite the highly electrophilic character of this reagent, it is remarkably tolerant of other functionalities providing it is used in the presence of a base such as a tertiary amine. All alcohols, regardless of their steric environment, are usually silylated with this reagent, an example being conversion of the ciguatoxin precursor 3 into its trimethylsilyl ether 4 (Scheme 2).[25]
Scheme 2 Silylation with Trimethylsilyl Trifluoromethanesulfonate[25]
I H O H OTBDMS
TMSOTf, Et3N CH2Cl2, 10 oC 98%
OTBDMS
HO
BnO
OTBDPS
TMSO
BnO
OTBDPS
To a soln of alcohol 3 (68.4 mg, 82.3 mol) and Et3N (45.9 L, 329 mol) in CH2Cl2 was added dropwise TMSOTf (31.8 L, 165 mol) at 10 8C, and the mixture was stirred at that temperature for 10 min. The reaction was quenched with sat. aq NaHCO3, and the aqueous layer was extracted repeatedly with Et2O. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane/EtOAc 15:1) to afford 4 as a pale yellow oil; yield: 72.8 mg (98%).
4.4.17.1.3
(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 (4):[25]
Method 3: Silylation of Alcohols with Trimethylsilyl Cyanide
of generating hydrogen cyanide if exposed to water or moisture. Many silyl cyanide derivatives are also volatile. All reactions involving the preparation or use of these compounds should be carried out by appropriately trained personnel in a well-ventilated fume hood and in full compliance with all local safety regulations regarding the use of cyanides.
CAUTION: All silyl cyanides should be treated as highly toxic in their own right, and are capable
for references see p 410
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Trimethylsilyl cyanide (TMSCN) is a reagent used for silylation where the presence of a base must be avoided.[26] Since the byproduct, hydrogen cyanide, is volatile and not sufficiently acidic to be deleterious, silylation can be carried out with the neat reagent or in a neutral solution. The reagent rapidly silylates alcohols, phenols and carboxylic acids, but reacts only slowly with amines and thiols. Amides are not silylated with this reagent. An example illustrating the application of this reagent is the conversion of the sensitive calicheamicinone precursor 5 into its trimethylsilyl ether 7 via the tris(silyl ether) 6 (Scheme 3).[27] It is noteworthy that only the primary trimethylsilyl ether of intermediate 6 is cleaved during workup in the presence of aqueous acetic acid.
Scheme 3 Silylation with Trimethylsilyl Cyanide[27]
OBoc
OBoc
NHCO2Me
NHCO2Me
TESO
Me3SiCN
TESO
OH
OTMS
HO
TMSO
OBoc
NHCO2Me
AcOH, H2O, THF 99%
TESO
OTMS
HO
A soln of 5 (465 mg, 0.85 mmol) in TMSCN (1 mL) was stirred for 30 min and the volatiles were evaporated in vacuo. The residue was dissolved in a mixture of THF (50 mL), H2O (10 mL), and glacial AcOH (1 mL). The mixture was stirred for 30 min (with close monitoring by TLC, Et2O/petroleum ether 1:1), diluted with Et2O (150 mL), washed with sat. aq NaHCO3 (2 50 mL), dried (MgSO4), filtered, and evaporated in vacuo to give 7 as a pale yellow, solid foam; yield: 518 mg (99%).
4.4.17.1.4
Methyl 11-(tert-Butoxycarbonyloxy)-13-(2-hydroxyethylidene)-1-(triethylsiloxy)-8(trimethylsiloxy)bicyclo[7.3.1]trideca-4,9,11-triene-2,6-diyn-10-ylcarbamate (7):[27]
Method 4: Silylation of Alcohols with N,O-Bis(trimethylsilyl)acetamide
hindered alcohols into their trimethylsilyl ethers when used in dimethylformamide at elevated temperature (80100 8C).[28] The byproduct acetamide must be removed, often requiring chromatography for purification of the silyl ether. The related reagent N,O-bis(trimethylsilyl)trifluoroacetamide,[29] although used less frequently, has the advantage that the byproduct, trifluoroacetamide, is removed more easily since it is quite volatile. An application of N,O-bis(trimethylsilyl)acetamide is seen in the conversion of the alcohol 8 into its trimethylsilyl ether 9 (Scheme 4), an intermediate in a synthetic route to azinomycin.[30]
N,O-Bis(trimethylsilyl)acetamide (BSA) is a relatively unselective reagent that can convert
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375
Scheme 4 Silylation with N,O-Bis(trimethylsilyl)acetamide[30]

AcHN CO2Me Br AcHN
CO2Me Br
AcO
BSA, THF, 90 oC, 1 h 92%
AcO
HO
NCbz
TMSO
NCbz
A soln of 8 (52 mg, 0.104 mmol) in THF (0.1 mL) was treated with BSA (15.2 L, 0.062 mmol, 1.2 equiv), and the mixture was warmed at 90 8C for 1 h. The reaction was cooled to 25 8C, diluted with EtOAc (25 mL), washed with sat. NaCl soln (2 2 mL), and the organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by Sephadex LH-20 chromatography to afford 9; yield: 54.5 mg (92%).
Cleavage
Methyl (2E,4S,5R)-4-Acetoxy-2-(acetylamino)-5-[(2S)-1-(benzyloxycarbonyl)aziridin-2-yl]-3bromo-5-(trimethylsiloxy)pent-2-enoate (9):[30]
4.4.17.1.5
Method 5: Cleavage of Trimethylsilyl Ethers with Acidic Reagents
Trimethylsilyl ethers are cleaved with exceptional ease under acidic conditions. Thus, it is quite feasible to unmask an alcohol protected as its trimethylsilyl ether without affecting other protected hydroxy functions; this includes alcohols protected in the form of virtually any other silyl ether. One acidic reagent that can be used to selectively cleave a trimethylsilyl ether is pyridinium 4-toluenesulfonate in methanol, as seen in the transformation of the sarcodictycine intermediate 10 to the alcohol 11 (Scheme 5).[31] Neither the triisopropylsilyl ether nor the 4-methoxybenzyl ether of 10 is removed under these conditions.
Scheme 5 Selective Cleavage of a Trimethylsilyl Ether[31]
PMBO
PMBO
OTMS
PPTS, MeOH rt, 30 min 94%
OH
OTIPS
OTIPS
10
11
Dilute hydrochloric acid can also be used to cleave trimethylsilyl ethers, although other silyl ethers such as triethylsilyl and tert-butyldimethylsilyl are vulnerable under these conditions. An example illustrating the facile cleavage of a trimethylsilyl ether in the presence of an epoxide is the deprotection of 12 to give epoxy alcohol 13 (Scheme 6).[32]
Scheme 6 Cleavage of a Trimethylsilyl Ether with Hydrochloric Acid[32]
O SiMe2Ph O
HCl, MeOH, CH2Cl2 0 oC, 30 min 90%
SiMe2Ph
OH
OTMS
OH
OH
( + )-12
( + )-13
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To a soln of 10 (3.2 mg, 4.7 mol) in MeOH (1 mL) was added, at 25 8C, PPTS (1.18 mg, 4.7 mol), and the mixture was allowed to stir at rt for 30 min. The reaction was quenched by the addition of sat. NaHCO3 soln (1 mL), then extracted with Et2O (2 10 mL). The combined organic extracts were dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (silica gel, EtOAc/hexane 15:85) to provide alcohol 11 as a colorless oil; yield: 2.7 mg (94%).
(1R,7S,8S,10R,14R)-7-Hydroxy-14-isopropyl-8-(4-methoxybenzyloxy)-7,11-dimethyl-3(triisopropylsiloxymethyl)bicyclo[8.4.0]tetradeca-2,11-dien-5-yn-4-one (11):[31]
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 (13):[32]
One drop of 1 M HCl was added to a soln of 12 (200 mg, 0.375 mmol) in MeOH (4 mL) and CH2Cl2 (2 mL) at 0 8C. The mixture was stirred for ca. 0.5 h at 0 8C and then extracted with CH2Cl2 (50 mL). The organic phase was washed with ice-cold H2O (2 20 mL), dried (Na2SO4), and the solvent was removed under reduced pressure to afford epoxy alcohol 13 as an unstable, yellow oil containing some (5%) aromatization product; yield: 156 mg (90%).
4.4.17.1.6
Method 6: Cleavage of Trimethylsilyl Ethers under Basic Conditions
One of the mildest methods for cleaving a trimethylsilyl ether is through its exposure to potassium carbonate in methanol, conditions which will not effect cleavage of any other silyl ether. The selective deprotection of the ciguatoxin precursor 14 bearing three different silyl ethers, as well as a benzyl ether and an epoxide, exemplifies an application of this method (Scheme 7).[33]
Scheme 7 Selective Cleavage of a Trimethylsilyl Ether with Base[33]
H O H OTBDMS
K2CO3, MeOH 0 oC, 1.5 h 96%
TMSO
BnO 14
OTBDPS
OTBDMS
HO
BnO
OTBDPS
15
The most widely used method for cleaving silyl ethers is through the use of tetrabutylammonium fluoride in tetrahydrofuran. This reagent can be used for cleaving trimethylsilyl ethers, but is not selective with respect to silyl ethers in general. Tetrabutylammonium fluoride is a sufficiently basic reagent to cause elimination and other side reactions with base-sensitive compounds, and it will sometimes promote migration of a silyl group to a neighboring free hydroxy group; however, esters are not usually cleaved with this reagent, as deprotection of the benzoate 16 reveals (Scheme 8).[34]
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Scheme 8 Cleavage of a Trimethylsilyl Ether with Tetrabutylammonium Fluoride[34]
O H
TBAF, THF, 0 oC 98%
Bn
O H
Bn
OTMS 16
OBz
OH
OBz
17
To a soln of 14 (5.2 mg, 5.50 mol) in MeOH (1 mL) was added K2CO3 (an excess amount) at 0 8C, and the mixture was stirred at the same temperature for 1.5 h. The mixture was diluted with Et2O, and H2O was added. The aqueous layer was extracted repeatedly with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane/EtOAc 3:1) to afford 15 as a colorless oil; yield: 4.6 mg (96%).
[2S-(2,3a,3b,6a,9a,9b,10,11a)]-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 (17):[34]
(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 (15):[33]
To a stirred soln of silyl ether 16 (8 mg, 12.4 mol) in THF (1 mL) at 0 8C was added 1.0 M TBAF in THF (24 L, 24.8 mol). After being stirred at 0 8C for 10 min, the mixture was poured into sat. aq NH4Cl (5 mL) and extracted with EtOAc (3 2 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. Purification by flash chromatography (EtOAc/hexanes 2:8) gave alcohol 17; yield: 6.9 mg (98%).
4.4.17.2
Triethylsilyl Ethers
Triethylsilyl (TES) ethers are more stable and more resistant to acidic cleavage than trimethylsilyl ethers. They are often used where exhaustive silylation of a polyol is desired, but where a per(trimethylsilyl ether) is too labile for purification. The volatility of a triethylsilyl ether is only slightly less than that of a trimethylsilyl ether; however, the increased size of the substituents at silicon in a triethylsilyl ether can make this silylation of a tertiary alcohol quite sluggish, especially with chlorotriethylsilane.
Formation
4.4.17.2.1
Method 1: Silylation of Alcohols with Chlorotriethylsilane
Triethylsilyl ethers are most frequently prepared using chlorotriethylsilane (TESCl)[35] in the presence of a base such as imidazole, pyridine or 4-(dimethylamino)pyridine.[36] A typical silylation with this reagent is that of alcohol 18 carried out in dimethylformamide at room temperature to give triethylsilyl ether 19 (Scheme 9).[37]
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Scheme 9 Silylation with Chlorotriethylsilane in the Presence of Imidazole[37]
OH O
TESCl, imidazole DMF, rt, 15 h 70%
PMBO
N Me
OMe
18
TESO
R S
TESO
R R
PMBO
N Me
OMe
PMBO
N Me
OMe
(3S)-19
89:11
(3R)-19
(2R,3S,4R)-N-Methoxy-5-(4-methoxybenzyloxy)-N,2,4-trimethyl-3-(triethylsiloxy)pentanamide (19):[37]
To a soln of a mixture of alcohol stereoisomers 18 (1.02 g, 3.14 mmol) in DMF (15 mL) were added imidazole (488 mg, 7.16 mmol) and TESCl (0.9 mL, 5.36 mmol) at rt. After being stirred for 15 h, the mixture was quenched with H2O. The organic layer was separated, washed with 0.5 M aq NaHSO4, sat. aq NaHCO3 and brine, dried (Na2SO4), and concentrated to give a residue which was purified by flash chromatography (silica gel, EtOAc/hexane 1:9) to give (3S)-19 as a colorless oil [yield: 855 mg (62%)] along with the 3R-diastereomer [yield: 106 mg (8%)].
4.4.17.2.1.1
Variation 1: With Chlorotriethylsilane in Pyridine
Chlorotriethylsilane is more reactive when used with pyridine as the solvent. For example, a relatively difficult silylation of the hindered alcohol 20 to give triethylsilyl ether 21, an intermediate in a zaragozic acid synthesis, was carried out with chlorotriethylsilane in pyridine at room temperature (Scheme 10).[38] The tertiary alcohol in 20 was unaffected under these conditions.
Scheme 10 Silylation with Chlorotriethylsilane in Pyridine[38]
O O
HO
OHC
CO2But OH
TESCl, py, rt, 22 h 82%
ButO2C
CO2But 20
TESO
OHC
CO2But OH
ButO2C
CO2But 21
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Alcohol 20 (48.2 mg, 71.9 mol) was dissolved in pyridine (2.5 mL), and the soln was cooled to 0 8C. A soln of TESCl (0.40 mL, 2.4 mmol) in pyridine (2.0 mL) was added over 5 min, after which the ice bath was removed and the soln was stirred at rt for 22 h. The mixture was diluted with Et2O (30 mL) and was washed with 0.5 M HCl (2 30 mL), sat. aq NaHCO3 (20 mL), H2O (20 mL), and brine (20 mL). The aqueous layers were back-extracted with Et2O (30 mL), and the combined organic layers were dried (MgSO4), filtered, and evaporated. The crude product was purified by flash chromatography (silica gel, gradient elution, EtOAc/hexanes 1:7 to 1:5) to give 21; yield: 46.3 mg (82%).
4.4.17.2.1.2
Tri-tert-butyl {1S-[1,3,4,5,6(2E,4S,6S),7]}-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 (21):[38]
Variation 2: With Chlorotriethylsilane in the Presence of 4-(Dimethylamino)pyridine
Chlorotriethylsilane together with 4-(dimethylamino)pyridine is often used for the silylation of sterically hindered secondary alcohols.[36] This combination with imidazole in dichloromethane at low temperature was effective in promoting a selective silylation of one of the two secondary alcohols in compound 22 to yield the mono(triethylsilyl ether) 23 (Scheme 11).[39] This selectivity, which was critical to a subsequent internal ketalization involving the free hydroxy group of 23, reflects the subtle steric factors that can impinge upon and differentiate the reactivity of cyclic and acyclic alcohols toward this silylating agent.
Scheme 11 Silylation with Chlorotriethylsilane in the Presence of 4-(Dimethylamino)pyridine[39]
OH
TESCl, DMAP, imidazole CH2Cl2, 78 oC, 3 h 98%
H O HO MeO
22
OTES
H O HO MeO
23
To a soln of alcohol 22 (210 mg, 420 mol) in CH2Cl2 (8.4 mL) at 78 8C were added imidazole (71 mg, 1.05 mmol), DMAP (10 mg), and TESCl (78 L, 70 mg, 462 mol). After 3 h at 78 8C, the mixture was quenched by the addition of sat. aq NaHCO3 (5 mL), and warmed to rt. The mixture was poured into EtOAc (25 mL) and then sat. aq NaHCO3 (25 mL). The phases were separated, and the aqueous layer was extracted with EtOAc (2 25 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography (EtOAc/hexane 45:55) afforded 23 as a clear oil; yield: 253 mg (98%).
(2S,2R,2R,3R,4R,5S,5S)-5-[(1R,2R,3S,4R)-1-Hydroxy-3-methoxy-2-methyl-4-(2-methyl1,3-dioxolan-2-yl)pentyl]-2,3,5-trimethyl-4-(triethylsiloxy)decahydro-2,2:5,2-terfuran-5(2H)-one (23):[39]
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4.4.17.2.2
Method 2: Silylation of Alcohols with Triethylsilyl Trifluoromethanesulfonate
Triethylsilyl trifluoromethanesulfonate (TESOTf)[40] is now available commercially. It is often employed for the triethylsilylation of less reactive alcohols and is invariably used in the presence of pyridine or a substituted pyridine. The conversion of alcohol 24 into its triethylsilyl ether 25, an intermediate in a route to various macrolides, illustrates an application of this reagent (Scheme 12).[41] The presence of both triethylsilyl and triisopropylsilyl ethers in 25 was a design element that permitted selective cleavage of the triethylsilyl ether at a later step in the synthesis.
Scheme 12
O O
Silylation with Triethylsilyl Trifluoromethanesulfonate[41]

OH OTIPS O O
TESOTf, 2,6-lut CH2Cl2, rt 99%
OTES OTIPS
Bn
Bn
24
25
To a soln of alcohol 24 (1.835 g, 3.74 mmol) in CH2Cl2 (75 mL) at rt was added 2,6-lutidine (0.653 mL, 5.61 mmol), followed by TESOTf (0.930 mL, 4.11 mmol). The resultant colorless soln was stirred for 40 min before the addition of sat. aq NaHCO3 (50 mL). The layers were separated, and the aqueous layer was extracted with CH2Cl2 (2 30 mL). The combined organic phases were washed with 1 M NaHSO4 (20 mL), H2O (20 mL), and brine (20 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The product was purified by flash chromatography (5 15 cm silica gel column, EtOAc/hexanes 1:9) to give 25 as a clear colorless oil; yield: 2.28 g (99%).
Cleavage
(4R)-4-Benzyl-3-[(2R,3S,4R,5R)-2,4-dimethyl-1-oxo-3-(triethylsiloxy)-5-(triisopropylsiloxy)hexyl]oxazolidin-2-one (25):[41]
4.4.17.2.3
Method 3: Cleavage of Triethylsilyl Ethers under Acidic Conditions
Although triethylsilyl ethers are more stable toward acidic reagents than their trimethylsilyl counterparts,[42] they can be cleaved under acidic conditions to give the parent alcohol in good yield. Hydrogen fluoridepyridine complex is a commonly used reagent for accomplishing this cleavage, and is often selective, as the example in Scheme 13 illustrates. Thus, the triethylsilyl ether of 26 was removed in the presence of hydrogen fluoridepyridine complex without affecting either the triisopropylsilyl ether or the benzylidene acetal in this structure.[41] The resultant alcohol 27 was obtained in nearly quantitative yield.
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381
Scheme 13
Cleavage of a Triethylsilyl Ether with Hydrogen FluoridePyridine Complex[41]

Ph
OTES OTIPS
HFpy, py, THF, 0 oC 95%
Bn
26
Ph
OH
OTIPS
Bn
27
To a soln of 26 (162.5 mg, 0.180 mmol) in THF (5 mL) at 0 8C in a Nalgene bottle was added ca. 4 mL of a HFpyridine stock soln [HFpyridine (2 mL), pyridine (4 mL), and THF (16 mL)]. After 2.5 h, the reaction was quenched by the dropwise addition of sat. aq NaHCO3 (50 mL), and the resultant mixture was stirred at 0 8C for 30 min. The mixture was then partitioned between CH2Cl2 (10 mL) and H2O (10 mL). The aqueous layer was separated and extracted with CH2Cl2 (5 10 mL). The combined organic layers were washed with 1 M aq NaHSO4, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (2 13.5 cm silica gel column, linear gradient 10 to 20% EtOAc/hexanes) to afford 27 as a clear colorless oil; yield: 135.2 mg (95%).
4.4.17.2.3.1
(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 (27):[41]
Variation 1: In the Presence of 4-Toluenesulfonic Acid
Highly selective cleavage of triethylsilyl ethers can be realized with the acidic catalyst 4toluenesulfonic acid in the presence of an alcohol such as methanol.[4] For example, the triethylsilyl ether 28 undergoes cleavage using these conditions without affecting the methoxymethyl, tert-butyldimethylsilyl, or 4-methoxybenzyl ethers present in this structure (Scheme 14). The resultant alcohol 29 is a pivotal intermediate in Marshalls synthesis of discodermolide.[43]
Scheme 14 Cleavage of Triethylsilyl Ethers Using 4-Toluenesulfonic Acid as a Catalyst[43]
TsOH, MeOH 0 oC, 1 h 72%
OPMB
OMOM OTBDMS
OPMB OTES
OMOM 28
OPMB
OMOM OTBDMS
OPMB OH
OMOM 29
b
382
To a cold (0 8C) soln of triethylsilyl ether 28 (40 mg, 0.035 mmol) in MeOH (5 mL) was added TsOHH2O (ca. 2 mg, 0.010 mmol). The resultant mixture was stirred for 1 h at 0 8C. Et3N (2 mL) was added, and the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (hexanes/EtOAc 4:1 to 2:1) to provide alcohol 29 as a clear oil; yield: 26 mg (72%).
4.4.17.2.3.2
(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)3,5,11,13,15,17,19,21-octamethylpentacosa-9,14,22,24-tetraen-2-one (29):[43]
Variation 2: With Trifluoromethanesulfonic Acid
Aqueous trifluoromethanesulfonic acid has been used to cleave a triethylsilyl ether with high selectivity, as in the conversion of 30 into the calicheamicinone precursor 31 (Scheme 15).[44] Neither the tert-butyldimethylsilyl ether nor any other acid-sensitive functionality was compromised in this process.
Scheme 15 Cleavage of Triethylsilyl Ethers with Trifluoromethanesulfonic Acid[44]
TBDMSO O TBDMSO O
BocO Boc2N
OTES
TfOH, H2O, THF, rt 95%
BocO Boc2N
OH
30
31
10-[Bis(tert-butoxycarbonyl)amino]-11-(tert-butoxycarbonyloxy)-1-(tert-butyldimethylsiloxy)-8-hydroxybicyclo[7.3.1]trideca-4,9,11-triene-2,6-diyn-13-one (31):[44]
To a soln of 30 (906 mg, 1.17 mmol) in THF (10.6 mL) under argon at rt was added dropwise a soln of TfOH (1.37 mL) in H2O (3.87 mL) by cannula with stirring. The mixture was stirred for 10 min, diluted with Et2O (50 mL), and washed with sat. aq NaHCO3 (20 mL). After drying (MgSO4) and evaporation of the solvents in vacuo, the product was purified by chromatography (silica gel, Et2O/hexanes 2:8) to give 31; yield: 730 mg (95%).
4.4.17.2.4
Method 4: Cleavage of Triethylsilyl Ethers with Tetrabutylammonium Fluoride
Triethylsilyl ethers are appreciably more stable to basic reagents than trimethylsilyl ethers and will survive conditions such as potassium carbonate in methanol;[41] however, they are readily cleaved with tetrabutylammonium fluoride in tetrahydrofuran. The rate of cleavage with this reagent is sufficiently rapid such that a triethylsilyl group can be removed without perturbing a more resistant ether, such as a tert-butyldiphenylsilyl ether. This is illustrated in the selective cleavage of the triethylsilyl ether in 32 to give alcohol 33, in which the tert-butyldiphenylsilyl ether as well as the 4-methoxybenzyl ether are retained (Scheme 16).[45]
b
4.4.17
Silyl Ethers
383
Scheme 16
Cleavage of Triethylsilyl Ethers with Tetrabutylammonium Fluoride[45]

OTBDPS
OTBDPS
TBAF, THF, 0 oC, 45 min 94%
MsO
MsO
PMBO
OTES
PMBO
OH
32
33
To a soln of 32 (167 mg, 180 mol) in THF (8 mL) at 0 8C was added a soln of 1.0 M TBAF in THF (270 L, 270 mol). The soln was stirred at 0 8C for 45 min then diluted with EtOAc (60 mL), washed with H2O (10 mL) and brine (10 mL), and the combined aqueous phases were extracted with EtOAc (10 mL). The combined organic phases were dried (MgSO4), filtered and concentrated by rotary evaporation. Flash chromatography (hexanes/EtOAc 2:1) afforded 33 as a colorless oil; yield: 137 mg (94%).
4.4.17.3
(7R)-5-O-(tert-Butyldiphenylsilyl)-7-{(2S)-4-[(2R)-2-hydroxy-4-(4-methoxybenzyloxy)butyl]-2(methylsulfonyloxy)pent-4-enyl}-1,2-O-isopropylidene-3,7-anhydro-4,6-dideoxy-d-riboheptitol (33):[45]
tert-Butyldimethylsilyl Ethers
The tert-butyldimethylsilyl (TBDMS) group[46] has become extremely popular among synthetic chemists as a protecting device for alcohols, and is now the most widely used silyl ether for this purpose. Both tert-butyldimethylsilyl chloride and tert-butyldimethylsilyl trifluoromethanesulfonate are effective silylating agents for primary alcohols and many secondary alcohols; tertiary alcohols are often resistant to silylation with these reagents. A wide variety of conditions has been developed for the preparation of tert-butyldimethylsilyl ethers, some of which permit selective silylation of seemingly similar hydroxy functions. tert-Butyldimethylsilyl ethers are much more stable toward basic reagents than are trimethylsilyl and triethylsilyl ethers. They are readily cleaved with tetrabutylammonium fluoride or hydrogen fluoridepyridine complex, however, and are sometimes removed in the course of reduction with hydride reagents such as lithium aluminum hydride and diisobutylaluminum hydride. tert-Butyldimethylsilyl ethers, although less sensitive toward acidic reagents than their trimethylsilyl counterparts, are nevertheless quite readily cleaved in the presence of acetic acid or trifluoroacetic acid. This mode of cleavage of tert-butyldimethylsilyl ethers can have the advantage of avoiding the strongly basic reaction medium associated with tetrabutylammonium fluoride.
Formation
4.4.17.3.1
Method 1: Silylation of Alcohols with tert-Butyldimethylsilyl Chloride
A widely employed method for the preparation of tert-butyldimethylsilyl ethers utilizes tert-butyldimethylsilyl chloride (TBDMSCl) together with imidazole in dimethylformamide at temperatures ranging from ambient to 80 8C.[46] Primary alcohols are readily silylated under these conditions, as exemplified in the conversion of the triol 34 into the tris(tert-butyldimethylsilyl ether) 35 (Scheme 17).[47]
b
384
Scheme 17 Silylation with tert-Butyldimethylsilyl Chloride and Imidazole[47]
O O NMe2
TBDMSCl, imidazole DMF, 70 oC 94%
NMe2
HO
OH
TBDMSO
OTBDMS
OH
OTBDMS
34
35
A mixture of the triol 34 (100 mg, 0.366 mmol), imidazole (177 mg, 2.6 mmol), and TBDMSCl (200 mg, 1.3 mmol) in dry DMF (5 mL) was kept at 70 8C overnight. The mixture was partitioned between Et2O and H2O, and the ethereal soln was washed thoroughly with H2O, dried (MgSO4), and evaporated. Purification on silica gel (Et2O) afforded 35 as a colorless liquid; yield: 214 mg (94%).
4.4.17.3.1.1
(4S,5E)-9-(tert-Butyldimethylsiloxy)-4,8-bis(tert-butyldimethylsiloxymethyl)-N,N,4-trimethylnon-5-enamide (35):[47]
Variation 1: In the Presence of 4-(Dimethylamino)pyridine
Silylation of more sterically hindered alcohols, such as 36, with tert-butyldimethylsilyl chloride requires replacement of imidazole (Section 4.4.17.3.1) with a stronger base such as 4-(dimethylamino)pyridine.[48] Under these conditions, 36 can be converted into its tertbutyldimethylsilyl ether 37 in high yield (Scheme 18).[49]
Scheme 18 Silylation with tert-Butyldimethylsilyl Chloride in the Presence of 4-(Dimethylamino)pyridine[49]
CN
TBDMSCl, DMAP DMF, 21 oC, 3 d 81%
CN
HO
TBDMSO
36
37
TBDMSCl (170 mg, 1.13 mmol) and DMAP (270 mg, 2.21 mmol). The resulting soln was stirred at 21 8C for 3 d. H2O was added, the mixture was extracted with Et2O, and the combined extracts were washed with brine, dried, and concentrated. The residual oil was chromatographed (petroleum ether/Et2O 19:1) to give 37; yield: 254 mg (81%).
4.4.17.3.1.2
rac-(5R)-5-[(1R,2E)-1-(tert-Butyldimethylsiloxy)penta-2,4-dienyl]-2,6,6-trimethylcyclohex-1eneacetonitrile (37):[49] To a soln of alcohol 36 (213 mg, 0.87 mmol) in dry DMF (5 mL) was added sequentially
Variation 2: In Dichloromethane
Replacement of dimethylformamide as the solvent (Section 4.4.17.3.1.1) by dichloromethane has the effect of moderating the reactivity of tert-butyldimethylsilyl chloride, so that the reagent becomes more selective in silylation of alcohols. Thus, the primary alcohol of 38 was protected as its tert-butyldimethylsilyl ether 39 in the course of work on lankacyclins by using dichloromethane as the solvent (Scheme 19).[50] An advantage of dichloromethane over dimethylformamide is its easier removal from the product, but since imi-
b
4.4.17
Silyl Ethers
385
dazole has diminished solubility in dichloromethane alternative bases, usually 4-(dimethylamino)pyridine or triethylamine, or sometimes both as in this case, are necessary to achieve a sufficiently reactive silylating agent.
Scheme 19 Silylation with tert-Butyldimethylsilyl Chloride in Dichloromethane[50]
CO2Me
TBDMSCl, Et3N DMAP, CH2Cl2 73%
CO2Me
OH
OH
OH
TBDMSO
38
39
Et3N (16 g, 0.158 mol), DMAP (0.6 g, 4.9 mmol) and TBDMSCl (20 g, 0.133 mol) were added to a soln of dihydroxy ester 38 (16.2 g, 0.121 mol) in CH2Cl2 (150 mL). The mixture was stirred overnight then poured into H2O. The two phases were separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. Chromatography of the residue gave 39 as an oil; yield: 22 g (73%).
4.4.17.3.2
Methyl (3S)-4-(tert-Butyldimethylsiloxy)-3-hydroxybutanoate (39):[50]
Method 2: Silylation of Alcohols with tert-Butyldimethylsilyl Trifluoromethanesulfonate
The more powerful silylating agent tert-butyldimethylsilyl trifluoromethanesulfonate (tert-butyldimethylsilyl triflate, TBDMSOTf) has become widely used for the preparation of tert-butyldimethylsilyl ethers in spite of the fact that it is more susceptible to degradation by moisture than tert-butyldimethylsilyl chloride and has a shorter storage lifetime.[51] One reason for the popularity of this reagent is that whereas silylation of alcohols can take many hours with tert-butyldimethylsilyl chloride, even with an excess of that reagent, it occurs in minutes with tert-butyldimethylsilyl trifluoromethanesulfonate. As a result, silylation with tert-butyldimethylsilyl trifluoromethanesulfonate can be carried out at low temperature, a feature that is used to advantage in selective silylation of two or more hydroxy groups in different steric environments. Thus, exposure of the steroidal diol 40 to tert-butyldimethylsilyl trifluoromethanesulfonate in the presence of pyridine at 78 8C results in virtually instantaneous silylation of the 3-hydroxy substituent to give 41 whilst leaving the D-ring hydroxy untouched (Scheme 20).[52] As in this example, silylation with tert-butyldimethylsilyl trifluoromethanesulfonate is almost always carried out in dichloromethane as the solvent.
Scheme 20 Silylation with tert-Butyldimethylsilyl Trifluoromethanesulfonate[52]
Ac
TBDMSOTf py, CH2Cl2, 78 oC 90%
Ac
OH
OH
HO
TBDMSO
40
41
3-(tert-Butyldimethylsiloxy)-15-hydroxy-5-pregn-16-en-20-one (41):[52]
To a soln of diol 40 (300 mg, 0.9 mmol) in pyridine (5 mL) and CH2Cl2 (5 mL) cooled to 78 8C was added dropwise a soln of TBDMSOTf (0.23 mL, 0.9 mmol) in CH2Cl2 (2 mL). Additional TBDMSOTf in CH2Cl2 soln was added (0.1 equiv at a time) until the reaction was
b
386
complete. The reaction was quenched at 78 8C by the addition of a sat. NH4Cl soln. The aqueous layer was extracted with EtOAc, and the extract was concentrated under vacuum. Purification of the residue by flash chromatography (silica gel, hexane/EtOAc 3:1) gave 41 as a white solid; yield: 363 mg (90%).
4.4.17.3.2.1
Variation 1: Selective Silylation of Phenols
Silylation with tert-butyldimethylsilyl trifluoromethanesulfonate at low temperature can be used to discriminate between phenols and aliphatic hydroxy functions, as in the conversion of 42 into the aryl silyl ether 43 (Scheme 21).[53] This reaction illustrates the general observation that phenols are converted into their tert-butyldimethylsilyl ethers more rapidly than are aliphatic alcohols.
Scheme 21 Selective Silylation, with tert-Butyldimethylsilyl Trifluoromethanesulfonate, of a Phenol in the Presence of an Aliphatic Alcohol[53]
OH
OBn
TBDMSOTf, 2,6-lut, CH2Cl2, 78 oC, 5 min
4'
MeO
OH
90% (2 steps from the 4'-OMEM derivative)
OMe
42
OH
OBn
MeO
OTBDMS
OMe
43
The crude diol 42 (16 mg, prepared in situ from the 4-OMEM derivative) was dissolved in CH2Cl2 (1 mL), to which was added 2,6-lutidine (26.1 mg, 0.24 mmol) and TBDMSOTf (38.1 mg, 0.14 mmol) at 78 8C. After the soln was stirred for 5 min, the reaction was quenched by adding pH 7 phosphate buffer, and the products were extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by preparative TLC (hexane/EtOAc 7:3) to give aryl silyl ether 43 as a pale yellow oil; yield: 13.0 mg (90% for 2 steps from the 4-OMEM derivative).
4.4.17.3.2.2
(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 (43):[53]
Variation 2: Selective Silylation of Alcohols
The effect of reaction temperature on selectivity in silylation with tert-butyldimethylsilyl trifluoromethanesulfonate can be striking, as seen in the conversion of triol 44 into the bis(tert-butyldimethylsilyl ether) 45 at 20 8C (Scheme 22).[54] Although both secondary hydroxy groups in this cis-fused decahydronaphthalene are equatorial, only the alcohol that is remote from the quaternary center is silylated. In structures such as 44, where two hydroxy substituents are in spatial proximity, the initial silylation of one hydroxy group will often retard reaction of the second hydroxy with this silylating agent, due to steric reasons. This will, of course, augment selectivity arising from a temperature effect.
b
4.4.17
Silyl Ethers
387
Scheme 22 Selective Silylation of Secondary Alcohols with tert-Butyldimethylsilyl Trifluoromethanesulfonate[54]

HO H OH
TBDMSOTf, Et3N DMAP, CH2Cl2 20 oC, 30 min 87%
HO
OTBDMS
HO
TBDMSO
44
45
To a stirred mixture of triol 44 (92 mg, 0.36 mmol), Et3N (109 mg, 1.08 mmol), and DMAP (2 mg, 0.016 mmol) in CH2Cl2 (5 mL) at 20 8C, was added TBDMSOTf (190 mg, 0.72 mmol). The mixture was stirred at 20 8C for 30 min, diluted with Et2O (40 mL), washed with 5% HCl (2 mL), brine (5 mL) and H2O (5 mL), dried (Na2SO4), and concentrated in vacuo. Flash chromatography of the residue (silica gel, EtOAc/hexane 5:95) afforded 45 as a colorless oil; yield: 152 mg (87%).
4.4.17.3.3
(1,3,4a,5,8,8a)-8-(tert-Butyldimethylsiloxy)-3-(tert-butyldimethylsiloxymethyl)-5isopropyl-3-methyldecahydro-1-naphthol (45):[54]
Method 3: Migration of a tert-Butyldimethylsilyl Group from a tert-Butyldimethylsilyl Ether to an Alcohol
The tert-butyldimethylsilyl group of a tert-butyldimethylsilyl ether will migrate to the oxygen atom of an adjacent alcohol under basic conditions if the new tert-butyldimethylsilyl ether is sterically less crowded than its precursor.[14] Thus, the direction of migration is invariably from a secondary to a primary alcohol or from a tertiary to either a secondary or primary alcohol. Migration between 1,2-substituted and 1,3-substituted diol derivatives is particularly common, although transfer of a tert-butyldimethylsilyl group between oxygens that span four or more carbons can occur if the oxygens are in spatial proximity.[16] The mechanism usually envisioned for these migrations involves intramolecular attack by an alkoxide oxygen on silicon to produce a pentacoordinate intermediate that collapses toward the more thermodynamically stable tert-butyldimethylsilyl ether. While silyl migration between oxygen atoms can pose an inconvenience in certain polyhydroxylated systems such as carbohydrates, where site-specific silylation may be desired, a virtue can be made of this chemistry in the deprotection of a silyl ether that may be difficult to cleave. Thus, if the silyl group can be forced to move to a less sterically crowded oxygen, its cleavage can become more facile. An example of an efficient migration of a tert-butyldimethylsilyl group is seen in the rearrangement of secondary tert-butyldimethylsilyl ether 46 to its isomeric primary silyl ether 47 (Scheme 23).[55]
Scheme 23 Rearrangement of a Secondary tert-Butyldimethylsilyl Ether to a Primary tert-Butyldimethylsilyl Ether[55]
OTBDMS
t-BuOK, THF/DMF (1:4) 78 oC, 4 h 99%
OH
F3C
OH
F3C
OTBDMS
46
47
Another example, in this case involving migration of the tert-butyldimethylsilyl group from a tertiary to a secondary alcohol, occurred in the course of an approach to the core structure of esperamicin A.[56] The rearrangement was triggered by S,S-diphenylsulfil-
b
388
imine used for the elaboration of the aziridine 49 from ,-unsaturated ketone 48 (Scheme 24).
Scheme 24 Migration of a tert-Butyldimethylsilyl Group to a Secondary Alcohol[56]
O O
HO
Ph2S
NHH2O
TBDMSO
CH2Cl2, rt, 16 h 60%
HN
TBDMSO
HO
MeO
MeO 49
48
A 0.5 M soln of alcohol 46 in a mixed solvent of THF and DMF (1:4) was reacted with tBuOK (1.1 equiv) at 78 8C. After stirring for 4 h at that temperature, the reaction was quenched with aq NH4Cl and extracted with Et2O (3 ). The combined extracts were dried (MgSO4), filtered, concentrated in vacuo, and purified by column chromatography (EtOAc/hexanes 14:86) to afford 47 in quantitative yield.
(+)-(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 (49):[56]
4-(tert-Butyldimethylsiloxy)-1,1,1-trifluorobutan-2-ol (47):[55]
To a soln of ketol 48 (59 mg, 0.16 mmol) in dry CH2Cl2 (5 mL) was added S,S-diphenylsulfilimine monohydrate (359 mg, 1.64 mmol), and the resulting suspension was stirred at rt for 16 h. The reaction was quenched with sat. NaHCO3 and extracted with CH2Cl2 (3 ). The combined organics were washed with H2O (2 ) and brine (1 ), dried (Na2SO4), filtered, and concentrated. The resulting crude material was subjected to flash chromatography (Et2O/heptane 1:1) to give aziridine 49 as white needles; yield: 36 mg (60%).
Cleavage
4.4.17.3.4
Method 4: Cleavage of tert-Butyldimethylsilyl Ethers with Tetrabutylammonium Fluoride
The most general method for cleaving tert-butyldimethylsilyl ethers is with tetrabutylammonium fluoride in tetrahydrofuran. Unhindered silyl ethers of this class are transformed quite readily to their respective alcohols with this reagent at room temperature.[46] Conversion of the bis(tert-butyldimethylsilyl ether) 50 into diol 51 illustrates this cleavage and demonstrates that a tert-butyldiphenylsilyl ether can be retained intact under these conditions (Scheme 25).[57]
b
4.4.17
Silyl Ethers
389
Scheme 25 Cleavage of Primary and Secondary tert-Butyldimethylsilyl Ethers with Tetrabutylammonium Fluoride[57]
TBDPSO
MeO
TBAF, THF, rt, 2 h 71%
NBoc O
OTBDMS O
TBDMSO
OMe
OMe
50
TBDPSO
MeO
NBoc O
OH
HO
OMe
OMe
51
More sterically crowded tert-butyldimethylsilyl ethers are sometimes stable toward tetrabutylammonium fluoride. For example, the tris(silyl ether) 52 undergoes selective cleavage of only one of the three secondary ether functions with tetrabutylammonium fluoride to afford hydroxy acid 53 (Scheme 26).[58] A possible explanation for this selectivity is intramolecular transfer of the most remote tert-butyldimethylsilyl group to the carboxylate formed when 52 is exposed to the basic fluoride reagent; subsequent acidic hydrolysis of the silyl ester would lead to 53.
Scheme 26 Fluoride[58] Selective Cleavage of a tert-Butyldimethylsilyl Ether with Tetrabutylammonium
TBDMSO
TBAF, THF 25 oC, 8 h 78%
OTBDMS CO2H
OTBDMS 52
TBDMSO
OH CO2H
OTBDMS 53
b
390
(4S,6R)-4-[(1R,2S,3E)-2-{[1-(tert-Butoxycarbonyl)-2-piperidyl]carbonyloxy}-4-[(1R,3R,4R)-4(tert-butyldiphenylsiloxy)-3-methoxycyclohexyl]-1,3-dimethylbut-3-enyl]-11-[(1E,4S,6S)-6{(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 (51):[57]
To a soln of bis(tert-butyldimethylsilyl ether) 50 (879 mg, 0.61 mmol) in THF (15 mL) was added 1 M TBAF in THF (1.84 mL, 1.84 mmol). After 2 h, the reaction was quenched with NH4Cl, and the THF was removed in vacuo. The product was extracted into EtOAc, and the organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The residue was chromatographed (silica gel, 2050% EtOAc/hexanes) to give diol 51; yield: 525 mg (71%).
(3S,6R,7S,12Z,15S,16E)-3,7-Bis(tert-butyldimethylsiloxy)-15-hydroxy-4,4,6,16-tetramethyl17-(2-methyl-1,3-thiazol-4-yl)-5-oxoheptadeca-12,16-dienoic Acid (53):[58]
A soln of tris(tert-butyldimethylsilyl ether) 52 (300 mg, 0.36 mmol) in THF (7.0 mL) at 25 8C was treated with 1 M TBAF in THF (2.2 mL, 2.2 mmol, 6.0 equiv). After being stirred for 8 h, the mixture was diluted with EtOAc (10 mL) and washed with 1 M aq HCl (10 mL). The aqueous soln was extracted with EtOAc (4 10 mL), and the combined organic phase was washed with brine (10 mL), dried (MgSO4), and concentrated. The crude mixture was purified by flash column chromatography (silica gel, MeOH/CH2Cl2 5:95) to provide hydroxy acid 53 as a yellow oil; yield: 203 mg (78%).
4.4.17.3.5
Method 5: Cleavage of tert-Butyldimethylsilyl Ethers with Tris(dimethylamino)sulfur (Trimethylsilyl)difluoride
Tris(dimethylamino)sulfur (trimethylsilyl)difluoride (TASF)[59] is a source of fluoride ion that is sometimes more effective than tetrabutylammonium fluoride (Section 4.4.17.3.4) for removing silyl ethers,[60] especially where the basicity associated with the latter reagent presents a problem. Thus, cleavage of the tert-butyldimethylsilyl ether 54 with tris(dimethylamino)sulfur (trimethylsilyl)difluoride gives the taxol precursor 55 in high yield (Scheme 27), whereas exposure of 54 to tetrabutylammonium fluoride results in cleavage of the benzoate as well as the silyl group.[61] Attempts to cleave the silyl ether of 54 with hydrogen fluoridepyridine complex led to products of rearrangement.
Scheme 27 Cleavage of a tert-Butyldimethylsilyl Ether with Tris(dimethylamino)sulfur (Trimethylsilyl)difluoride[61]
AcO AcO O O
OBOM
OBOM
TBDMSO
TASF, THF, rt, 1 h 94%
HO
HO
BzO 54
HO
AcO
BzO
AcO
55
A soln of silyl ether 54 (16.3 mg, 19.9 mol) in THF (0.5 mL) was added to TASF (37 mg, 0.134 mmol) at rt under a N2 atmosphere. The mixture was stirred for 1 h, diluted with EtOAc, poured into sat. aq NaHCO3 (20 mL) and extracted with CHCl3 (3 30 mL). The combined organic phase was dried (Na2SO4) and concentrated under reduced pressure to give a pale yellow oil (16 mg), which was filtered through a pad of silica gel using EtOAc/hexane (7:3) as eluent. The filtrate was concentrated to give diol 55; yield: 13.5 mg (94%).
7-O-(Benzyloxymethyl)baccatin III (55):[61]
b
4.4.17
Silyl Ethers
391
4.4.17.3.6
Method 6: Cleavage of tert-Butyldimethylsilyl Ethers under Acidic Conditions
A wide variety of acidic reagents has been used for the cleavage of tert-butyldimethylsilyl ethers. Several of these reagents exhibit good selectivity for the removal of a particular tert-butyldimethylsilyl ether while leaving other silyl ethers, even a trimethylsilyl ether, intact. For example, exposure of the bis(silyl ether) 56 to hydrofluoric acid in acetonitrile cleaves the primary tert-butyldimethylsilyl ether but does not alter the angular trimethylsilyl ether (Scheme 28).[34] The resulting alcohol 57 would have been difficult to obtain from 56 by other silyl ether cleavage methods; the selectivity observed probably reflects more facile protonation of the primary ether oxygen.
Scheme 28 Selective Cleavage of a tert-Butyldimethylsilyl Ether with Hydrofluoric Acid[34]
Ac O Ac O O O
49% aq HF MeCN, 0 oC, 6 min 90%
OTMS
OTBDMS
OTMS
OH
56
57
49% Aq HF (4.0 mL) was added dropwise to a soln of the silyl ether 56 (1.30 g, 2.23 mmol) in MeCN (30 mL) at 0 8C. After being stirred for 6 min, the mixture was quenched with sat. aq NaHCO3 (CAUTION: careful addition was required until the evolution of CO2 was no longer observed), diluted with H2O (150 mL), and extracted with EtOAc (3 100 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. Purification by flash chromatography (EtOAc/hexanes 1:1) gave the alcohol 57; yield: 0.934 g (90%).
4.4.17.3.6.1
(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 (57):[34]
Variation 1: With Hydrogen FluoridePyridine Complex
Hydrogen fluoridepyridine complex, a reagent which is often used in a mixed solvent system comprising pyridine and tetrahydrofuran, is highly effective for the cleavage of tert-butyldimethylsilyl ethers.[62] In general, primary tert-butyldimethylsilyl ethers are cleaved much more rapidly than their secondary or tertiary ether counterparts with hydrogen fluoridepyridine complex, and selective cleavage is usually possible with this reagent. Reaction temperature is the critical factor in achieving selective cleavage in these cases. A representative silyl ether cleavage with hydrogen fluoridepyridine complex is the conversion of the chlorothricolide intermediate 58 into the primary alcohol 59 (Scheme 29).[63] None of the other functional or protecting groups of thioester 58 (which was a mixture of two diastereomers resulting from the convergence of racemic subunits) are affected by this reagent.
b
392
Scheme 29 Complex[63] Cleavage of a tert-Butyldimethylsilyl Ether with Hydrogen FluoridePyridine
SEMO O TBDMSO O MeO O O O H + diastereomer
HFpy, py THF, rt, 2 h 97%
PhS
OMOM
58
SEMO
HO
MeO O
O H
diastereomer
PhS
OMOM
59
To a rapidly stirred soln of the thioester 58 (mixture of 2 diastereomers; 762 mg, 0.83 mmol) in THF (1 mL) was added a HFxpyridine soln [5 mL, prepared by diluting Aldrich HFxpyridine (13 g) with pyridine (31 mL) and THF (100 mL)], and the resulting mixture was stirred at rt for 2 h. After the mixture was poured into sat. NaHCO3 (50 mL), the aqueous layer was extracted with Et2O (3 100 mL) and the combined organic layers were dried (MgSO4). After removal of the solvent at reduced pressure, the crude residue was chromatographed (size C Lobar silica gel column, EtOAc/petroleum ether 28:72) to give the faster eluting alcohol 59 as a colorless oil; yield: 289 mg (43%). Further elution afforded the diastereomeric alcohol as a colorless oil; yield: 360 mg (54%).
4.4.17.3.6.2
rac-[1(5S*,6S*,8R*,9R*),2,4a,5,8a]-6-(Hydroxymethyl)-4-methoxy-9-methyl-2-oxo-8[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 (59):[63]
Variation 2: With Mineral Acid
A solution of a mineral acid such as hydrochloric acid can accomplish selective cleavage of certain silyl ethers, including tert-butyldimethylsilyl ethers.[64] An illustration of this selectivity is seen in the reaction of the differentially protected tetrakis(silyl ether) 60 with 10% hydrochloric acid, which leads to the diol 61 (Scheme 30).[65] Only the trimethylsilyl and tert-butyldimethylsilyl ethers are cleaved under these conditions, the triisopropylsilyl and tert-butyldiphenylsilyl ethers being unreactive.
b
4.4.17
Silyl Ethers
393
Scheme 30
Selective Cleavage of a tert-Butyldimethylsilyl Ether with Hydrochloric Acid[65]
10% aq HCl THF, rt, 3 h 87%
TIPSO
OTMS TBDPSO
Pri
OTBDMS
60
TIPSO
OH TBDPSO
Pri
OH
61
To a soln of tetrakis(silyl ether) 60 (0.41 g, 0.36 mmol) in THF (40 mL) was added 10% aq HCl (5.5 mL). The mixture was stirred at rt for 3 h and cooled to 0 8C. Solid NaHCO3 was added carefully in small portions until all the bubbling subsided. The aqueous layer was extracted with Et2O (4 20 mL), and the combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. Purification of the residue by column chromatography (silica gel, 510% EtOAc/hexanes) provided diol 61 as a white foam; yield: 0.30 g (87%).
4.4.17.3.6.3
(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 (61):[65]
Variation 3: With Organic Acids
Organic acids used for cleavage of tert-butyldimethylsilyl ethers include formic,[66] acetic,[67] trifluoroacetic,[68] and certain sulfonic acids.[69] Formic acid is the least selective of these reagents, showing little discrimination in the cleavage of tert-butyldimethylsilyl ethers in different steric or electronic environments. An example of a deprotection with this reagent is the reaction of the bis(tert-butyldimethylsilyl ether) 62 to give lankacidin C (63, Scheme 31).[66]
Scheme 31 Cleavage of tert-Butyldimethylsilyl Ethers with Formic Acid[66]
O O
HN
HCO2H, THF H2O, rt, 3 h 86%
HN
TBDMSO
OTBDMS
HO
OH
62
63
The use of trifluoroacetic acid for cleavage of tert-butyldimethylsilyl ethers is confined to compounds that are stable to a moderately strong acid, but the reagent can offer a valuable means for selective cleavage of these ethers. For example, the bis(tert-butyldimethyl-
b
394
silyl ether) 64 undergoes selective scission with trifluoroacetic acid, giving alcohol 65 in high yield (Scheme 32).[70] The more sterically hindered secondary silyl ether of 64 remains unaffected by this reagent.
Scheme 32 Selective Cleavage of a tert-Butyldimethylsilyl Ether with Trifluoroacetic Acid[70]
OTBDMS
MeO
OMe
OTBDMS
MeO
TFA, THF H2O, 0 oC, 3 h 91%
OMe N
MeO
64
OH
MeO
OMe
OTBDMS
MeO
OMe N
MeO
65
Selectivity in the cleavage of tert-butyldimethylsilyl ethers can also be achieved with 10camphorsulfonic acid. Thus, the secondary silyl ether but not the angular silyl ether of compound 66 is removed with 10-camphorsulfonic acid in dichloromethane containing a small amount of methanol to afford the diol 67 in excellent yield (Scheme 33).[71]
Scheme 33 Selective Cleavage of a tert-Butyldimethylsilyl Ether with 10-Camphorsulfonic Acid[71]
HO H OTBDMS HO H OH
CSA, CH2Cl2, MeOH, 25 oC, 1 h 100%
OTBDMS
OTBDMS
66
67
A soln of bis(silyl ether) 62 (15 mg, 0.022 mmol) in a mixture of THF/HCO2H/H2O (6:3:1, 2.0 mL) was stirred at rt for 3 h. The mixture was cooled to 0 8C and neutralized with sat. aq NaHCO3 (2 mL). This mixture was poured into EtOAc (10 mL) and brine (10 mL). The aqueous layer was extracted with EtOAc (10 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. Purification by preparative TLC (EtOAc) gave lankacidin C (63) as a white solid; yield: 8.7 mg (86%).
Lankacidin C (63):[66]
b
4.4.17
Silyl Ethers
395
A soln of bis(silyl ether) 64 (42 mg, 0.051 mmol) in THF (2 mL) containing TFA/H2O (9:1, 400 L) was stirred at 0 8C for 3 h. Sat. NaHCO3 (5 mL) was added, and the mixture was extracted with Et2O (3 10 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure; the residue was purified by flash chromatography (hexanes/EtOAc 3:1) to give alcohol 65 as a colorless, viscous oil; yield: 33 mg (91%).
(3aR,4R,5S,7aS)-7a-(tert-Butyldimethylsiloxy)-5-hydroxy-4-(hydroxymethyl)-4-methyl3a,4,5,7a-tetrahydroisobenzofuran-1(3H)-one (67):[71]
(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-dien1-ol (65):[70]
A soln of alcohol 66 (43.9 g, 99 mmol) in CH2Cl2 (250 mL) and MeOH (20 mL) was treated with CSA (0.52 g, 2.24 mmol) and stirred at 25 8C for 1 h. After dilution with CH2Cl2 (300 mL), the reaction was quenched with aq NaHCO3 (150 mL). The organic layer was separated, and the aqueous layer was extracted with Et2O (2 200 mL). The combined organic layer was dried (Na2SO4), concentrated, and purified by flash chromatography (silica gel, Et2O/petroleum ether 1:1) to give diol 67 as white crystals; yield: 32.6 g (100%).
4.4.17.3.6.4
Variation 4: With Lewis Acids
Lewis acids have found limited use as reagents for cleaving silyl ethers, in part because they coordinate weakly with the oxygen atom of ethers of this class; however, they can sometimes effect a remarkably efficient cleavage of a tert-butyldimethylsilyl ether,[72] as in the conversion of silyl ether 68 into alcohol 69 with boron trifluoridediethyl ether complex (Scheme 34).[73] A noteworthy feature of this transformation is that the trisubstituted epoxide of 68 does not suffer rearrangement to a ketone under the reaction conditions.
Scheme 34 Cleavage of a tert-Butyldimethylsilyl Ether with Boron TrifluorideDiethyl Ether Complex[73]
O O
BnO
BF3OEt2, CH2Cl2 010 oC 92%
BnO
OTBDMS
OH
68
69
To a soln of silyl ether 68 (53 mg, 0.10 mmol) in dry CH2Cl2 (8 mL) was added BF3OEt2 (63 L, 0.50 mmol) at 0 8C under N2. The mixture was allowed to warm to ca. 10 8C and was then stirred for 6 h. The reaction was quenched with sat. aq NH4Cl (2 mL), and the aqueous phase was extracted with CH2Cl2 (3 10 mL). The combined organic extracts were washed with brine (2 mL), dried (MgSO4), and filtered. Concentration of the filtrate followed by flash column chromatography (hexane/EtOAc 7:1) gave alcohol 69 as a white solid; yield: 38 mg (92%).
(4a,8a,9a)-1-Benzyloxy-6-hydroxy-4,6a,7a,9b-tetramethyldodecahydrophenanthro[2,3-b]oxirene-2,7-dione (69):[73]
b
396
4.4.17.4
Triisopropylsilyl Ethers
Triisopropylsilyl (TIPS) ethers are used as protection for primary and certain secondary alcohols,[74] the large steric bulk of the silyl group ensuring good selectivity in most instances.[75] Secondary alcohols can only be converted into their triisopropylsilyl ethers under more forcing conditions, and tertiary alcohols in general cannot be converted into triisopropylsilyl ethers. A principal advantage of triisopropylsilyl ethers is their stability toward basic conditions which cause cleavage of other functional groupings, including silyl ethers such as tert-butyldimethylsilyl.[76] Thus, esters can be saponified without destruction of a triisopropylsilyl ether, and strong bases such as tert-butyllithium, which can deprotonate the methyl group of a tert-butyldimethylsilyl ether, are without effect on a triisopropylsilyl ether. The triisopropylsilyl ether is among the weakest of the silyl ethers in terms of coordination to metal cations.[77] It is advisable not to use an excess of silylating agent, since it is sometimes contaminated with the more reactive, isomeric diisopropyl(propyl)silyl reagent.[78]
Formation
4.4.17.4.1
Method 1: Silylation of Alcohols with Triisopropylsilyl Trifluoromethanesulfonate and 2,6-Lutidine
The large steric demand imposed by the triisopropylsilyl group makes triisopropylsilyl trifluoromethanesulfonate (TIPSOTf) the most useful reagent for silylations in this class. In the presence of 2,6-lutidine and with dichloromethane as solvent, it is generally feasible to convert a primary alcohol into its triisopropylsilyl ether without affecting a secondary alcohol.[51] The conversion of diol 70 containing a primary and secondary hydroxy substituent into its mono(silyl ether) 71 reflects the selectivity that can be attained with this reagent (Scheme 35).[79]
Scheme 35 Selective Silylation of a Primary Alcohol with Triisopropylsilyl Trifluoromethanesulfonate[79]
HO TIPSO
OH
TIPSOTf, 2,6-lut CH2Cl2, 8 oC 91%
OH
70
71
To a soln of the diol 70 (5.28 g, 18 mmol) and 2,6-lutidine (3.15 mL, 27 mmol) in CH2Cl2 (25 mL) was added a soln of TIPSOTf (4.85 mL, 18 mmol) in CH2Cl2 (5 mL) over 1 h at 8 8C. After the mixture had been stirred for 4 h, the reaction was quenched by the addition of aq NaHCO3. After separation of the organic layer, the aqueous layer was extracted with EtOAc (2 ). The combined extracts were washed with brine and evaporated to dryness. The residue was purified by column chromatography (silica gel, hexane/EtOAc 5:1) to give alcohol 71; yield: 7.47 g (91%).
(4aR,5R,6RS,8aR)-6-Hydroxy-5,8a-dimethyl-5-[2-(triisopropylsiloxy)ethyl]octahydronaphthalen-1(2H)-one Ethylene Ketal (71):[79]
b
4.4.17
Silyl Ethers
397
4.4.17.4.1.1
Variation 1: With Triisopropylsilyl Trifluoromethanesulfonate in the Presence of 4-(Dimethylamino)pyridine
As with other silylating agents, triisopropylsilyl trifluoromethanesulfonate becomes more reactive when used in the presence of 4-(dimethylamino)pyridine, especially when pyridine is the solvent. Under these conditions, secondary alcohols are converted into their triisopropylsilyl ethers rapidly and in high yield. The silylation of diol 72 to give the tris(silyl ether) 73 illustrates this increased reactivity of the silylating agent (Scheme 36).[80]
Scheme 36 nate[80] Silylation of Secondary Alcohols with Triisopropylsilyl Trifluoromethanesulfo-
HO
HO
TIPSOTf DMAP, py, rt, 15 h 99%
TBDPSO
72
TIPSO TIPSO
TBDPSO
73
Diol 72 (125 mg, 0.200 mmol) was combined with DMAP (44 mg, 0.36 mmol) under a N2 atmosphere and then dissolved in dry pyridine (0.6 mL). TIPSOTf (0.4 mL, 1.49 mmol) was added via syringe, and the mixture was stirred for 15 h. Excess TIPSOTf was consumed by the addition of dry MeOH (1.5 mL). After 15 min, the reaction was transferred to a separatory funnel with Et2O and washed first with 5% HCl (15 mL) and then with a mixture of sat. aq NaHCO3 and brine (1:1, 20 mL). The aqueous layers were extracted with Et2O (2 40 mL), and the combined organics were dried (MgSO4). Filtration through a short silica gel plug with additional Et2O, and concentration in vacuo provided the crude, fully protected lactone which was purified by chromatography (silica gel, Et2O/hexanes 1:3) to afford 73 as a pale yellow oil; yield: 187 mg (99%).
Cleavage
(1S,1S,3R,5S,5S,6S,6S)-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) (73):[80]
4.4.17.4.2
Method 2: Cleavage of Triisopropylsilyl Ethers with Tetrabutylammonium Fluoride
The most general method for cleavage of a triisopropylsilyl ether is with tetrabutylammonium fluoride, however, this reagent typically exhibits no selectivity between silyl ethers of this class that are situated in different structural environments. Nevertheless, it is possible to retain a triisopropylsilyl ether while a more susceptible silyl ether, including a secondary tert-butyldiphenylsilyl ether, is cleaved with this reagent (see Scheme 48, Section 4.4.17.5.4). The conventional protocol for removing a triisopropylsilyl ether is illusfor references see p 410
b
398
trated in the conversion of 74 into diol 75 (Scheme 37), a late intermediate in a synthesis of milbemycin D.[65]
Scheme 37 Cleavage of a Triisopropylsilyl Ether with Tetrabutylammonium Fluoride[65]
TBAF THF, rt 95%
TIPSO
OH
Pri
74
HO
OH
Pri
75
(4S,6R,25R)-25-Isopropyl-5-O-demethyl-28-deoxy-3,4-dihydro-6,28-epoxymilbemycin B (75):[65]
1 M TBAF in THF (0.23 mL, 0.23 mmol) was added to a soln of macrolactone 74 (0.054 g, 0.075 mmol) in THF (1.0 mL). The resulting soln was stirred overnight at rt, concentrated in vacuo, and purified by column chromatography (silica gel, 1050% EtOAc/hexanes) to afford diol 75 as a white foam; yield: 0.040 g (95%).
4.4.17.4.3
Method 3: Cleavage of Triisopropylsilyl Ethers with Tris(dimethylamino)sulfur (Trimethylsilyl)difluoride
Tris(dimethylamino)sulfur (trimethylsilyl)difluoride (TASF) as a source of fluoride ion has been used to cleave triisopropylsilyl ethers in situations where the basicity of tetrabutylammonium fluoride would be destructive toward other functionality. An example in which only tris(dimethylamino)sulfur (trimethylsilyl)difluoride could be employed to successfully cleave a triisopropylsilyl ether is seen in the conversion of 76 into baccatin III (78, Scheme 38).[81] Cleavage of the silyl ether to yield alcohol 77 was followed by treatment with phenyllithium, which removed the 2,2,2-trichloroethoxycarbonyl (Troc) protection and opened the cyclic carbonate en route to triol 78 (accompanied by a 46% yield of 10-O-deacetylbaccatin III).
b
4.4.17
Silyl Ethers
399
Scheme 38 Cleavage of a Triisopropylsilyl Ether with Tris(dimethylamino)sulfur (Trimethylsilyl)difluoride[81]

AcO O OTroc AcO O OTroc
TASF, THF, 0 oC, 5 min 96%
TIPSO
H O OAc
HO
H O OAc
O 76
O 77
AcO
10
OH
PhLi, THF 33%
HO
O H HO BzO OAc 78
To silyl ether 76 (3.2 mg, 4 mol) in THF (0.8 mL) at 0 8C was added TASF (4.0 mg, 15 mol), and the mixture was stirred for 5 min at 0 8C. The reaction was quenched by addition of sat. aq NaHCO3. The aqueous layer was extracted with Et2O. The combined organic layers were washed with H2O and sat. brine, and then dried (anhyd Na2SO4). The crude mixture was filtered and concentrated under reduced pressure. Purification of the resultant residue by flash chromatography (silica gel, EtOAc/hexanes 3:7) provided alcohol 77; yield: 2.5 mg (96%).
4.4.17.4.4
[3aS-(3a,5,8,9a,10,11a,13a,13b,13c)]-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-dodecahydro3aH-oxeto[2,3:5,6]benzo[1,2:3,4]cyclodeca[1,2-d]-1,3-dioxol-10-yl 2,2,2-Trichloroethyl Carbonate (77):[81]
Method 4: Cleavage of Triisopropylsilyl Ethers with Hydrogen FluoridePyridine Complex
Hydrogen fluoridepyridine complex, used in a mixed tetrahydrofuran/pyridine solvent system, affords a convenient method for removing the triisopropylsilyl residue from oxygen. The final step in a synthesis of the immunosuppressant rapamycin (80) involved unmasking of both a triisopropylsilyl and a tert-butyldimethylsilyl ether, for which hydrogen fluoridepyridine complex treatment of 79 served well (Scheme 39).[82]
b
400
Scheme 39 Cleavage of a Triisopropylsilyl and a tert-Butyldimethylsilyl Ether with Hydrogen FluoridePyridine Complex[82]
TIPSO MeO OMe O O O O TBDMSO
HFpy, py, THF 0 oC to rt, 48 h 69%
O O
O HO
MeO
79
HO
MeO
OMe
HO
()-80
At 0 8C a soln of synthetic hemiketal ()-79 (5.1 mg, 4.3 mol) in THF (0.5 mL) was treated with pyridine (0.5 mL) followed by HFpyridine (0.5 mL). The mixture was warmed to rt, stirred for 48 h, and then partitioned between Et2O (10 mL) and H2O (10 mL). The organic phase was washed with sat. aq CuSO4 (5 mL), sat. aq NaHCO3 (5 mL), H2O (5 mL), and brine (5 mL), dried (MgSO4), filtered, and concentrated. Flash chromatography (hexanes/EtOAc 1:1 then 1:3) provided synthetic rapamycin (80) as a clear oil; yield: 2.7 mg (69%). Recrystallization (acetone/hexanes 4:6) gave ()-80 as a white solid.
4.4.17.4.5
()-Rapamycin (80):[82]
Method 5: Cleavage of Triisopropylsilyl Ethers under Acidic Conditions
Although acidic conditions are not often used to cleave triisopropylsilyl ethers, available evidence suggests that silyl ethers of this class are quite susceptible to cleavage in the presence of acidic reagents.[76,83] Thus, the triisopropylsilyl blocking group was removed from the mycotrienin precursor 81 with 4-toluenesulfonic acid in methanol to yield alcohol 82 without affecting the adjacent tert-butyldimethylsilyl ether (Scheme 40).[84] The sensitive triene unit of 81 was also stable under these conditions.
b
4.4.17
Silyl Ethers
401
Scheme 40
Selective Cleavage of a Triisopropylsilyl Ether under Acidic Conditions[84]

OMe
TsOH, MeOH, rt, 30 min 90%
NH
TBDMSO
OMe
TIPSO
OMe
81
OMe
NH
TBDMSO
OMe
HO
OMe
82
A soln of triene 81 (50 mg, 0.066 mmol) in MeOH (6.0 mL) was treated with catalytic TsOH (3.0 mg, 0.017 mmol, 0.25 equiv). The mixture was stirred at rt for 30 min and subsequently diluted with NaHCO3 and H2O (20 mL). The mixture was extracted with EtOAc (3 25 mL), dried (MgSO4), and concentrated in vacuo. Purification on silica gel (20 to 30% EtOAc/petroleum ether) afforded alcohol 82 as a colorless oil; yield: 36 mg (90%).
4.4.17.5
(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 (82):[84]
tert-Butyldiphenylsilyl Ethers
The tert-butyldiphenylsilyl (TBDPS) ether as a masking device for alcohols was introduced by Hanessian in order to provide a protecting group more stable toward acidic reagents than other silyl ethers.[85] tert-Butyldiphenylsilyl ethers are inert under acidic conditions which can cleave tert-butyldimethylsilyl ethers, and they typically survive those acidic reagents used to cleave alkyl ethers such as trityl and tetrahydropyranyl. The diminished reactivity of tert-butyldiphenylsilyl ethers toward electrophiles is thought to be due to the electron-withdrawing effect of the phenyl substituents attached to silicon. However, the tert-butyldiphenylsilyl group is more easily cleaved than the tert-butyldimethylsilyl group with sodium hydroxide.[86]
Formation
4.4.17.5.1
Method 1: Silylation of Alcohols with tert-Butyldiphenylsilyl Chloride
Both primary and secondary alcohols can be converted into their tert-butyldiphenylsilyl ethers, the usual reagent for this being the chlorosilane (tert-butyldiphenylsilyl chloride, TBDPSCl). Secondary alcohols, if sterically hindered, may require elevated reaction temperatures for efficient silylation with this reagent, as seen in the protection of ethyl (2S)-2hydroxy-3-methylbutanoate (83) as its tert-butyldiphenylsilyl ether 84 (Scheme 41).[85]
b
402
Scheme 41 Silylation of a Secondary Alcohol with tert-Butyldiphenylsilyl Chloride[87]
TBDPSCl, imidazole DMF, 80 oC, 7 h 92%
CO2Et
CO2Et
OH 83
OTBDPS 84
To a soln of ethyl (2S)-2-hydroxy-3-methylbutanoate (83; 2.22 g, 15.2 mmol) in DMF (20 mL) were added imidazole (1.24 g, 18.2 mmol) and TBDPSCl (5.00 g, 18.2 mmol) and the mixture was stirred at 80 8C. After being stirred for 7 h, the mixture was diluted with H2O (60 mL) and extracted with CH2Cl2 (3 60 mL). The combined extracts were washed with brine, dried (MgSO4), and concentrated in vacuo. Column chromatography (silica gel, hexane) gave silyl ether 84 as a colorless oil; yield: 5.40 g (92%).
4.4.17.5.1.1
Ethyl (2S)-2-(tert-Butyldiphenylsiloxy)-3-methylbutanoate (84):[87]
Variation 1: In the Presence of 4-(Dimethylamino)pyridine
Silylation with tert-butyldiphenylsilyl chloride can be carried out at room temperature if 4-(dimethylamino)pyridine is included in the reaction mixture,[88] as seen in the quantitative conversion of the hydroxyspiroketal 85 into its silyl ether 86 (Scheme 42).[65]
Scheme 42 Silylation with tert-Butyldiphenylsilyl Chloride in the Presence of 4-(Dimethylamino)pyridine[65]
TBDPSCl, DMAP imidazole, DMF, 25 oC, 60 h 100%
HO
TBDPSO
Pr
Pri
85
86
To a soln of alcohol 85 (4.470 g, 17.6 mmol), imidazole (2.64 g, 38.7 mmol) and DMAP (220 mg, 1.8 mmol) in dry DMF (300 mL) at 25 8C was added TBDPSCl (4.83 g, 17.6 mmol), and the mixture was stirred for 60 h. To this soln was added pentane (500 mL) and H2O (300 mL). The aqueous phase was extracted with pentane (2 100 mL), and the organic extracts were combined and dried (Na2SO4). The extracts were concentrated and the residue was purified by flash chromatography to give silyl ether 86 as a clear viscous oil; yield: 8.67 g (100%).
4.4.17.5.1.2
(2R,3S,8S,10S)-10-(tert-Butyldiphenylsiloxy)-2-isopropyl-3-methyl-8-vinyl-1,7dioxaspiro[5.5]undecane (86):[65]
Variation 2: Using Butyllithium
The reaction of butane-1,4-diol (87) with tert-butyldiphenylsilyl chloride at 78 8C using butyllithium as a base gives the monosilylation product 88 in high yield (Scheme 43).[89] This useful method of desymmetrizing a diol is undoubtedly assisted by the large steric bulk of the tert-butyldiphenylsilyl group.
b
4.4.17
Silyl Ethers
403
Scheme 43 Monosilylation of Butane-1,4-diol with tert-Butyldiphenylsilyl Chloride and Butyllithium[89]

OH
TBDPSCl (0.33 equiv), BuLi (0.33 equiv) THF, 78 oC to rt 90%
OTBDPS
HO
HO
87
88
A soln of butane-1,4-diol (6.0 g, 66.6 mmol) in THF (35 mL) was cooled to 78 8C under N2, and the resulting white suspension was treated in dropwise fashion, with vigorous stirring, with 2.5 M BuLi in hexanes (8.9 mL, 22.2 mmol, 0.33 equiv). The mixture became very viscous. After being stirred for an additional 5 min, the mixture was treated in dropwise fashion with TBDPSCl (5.76 mL, 22.2 mmol, 0.33 equiv), and the resulting mixture was allowed to warm to rt, which gave a white suspension. After being stirred at rt for 40 min, the mixture was treated with H2O (35 mL) and sat. aq NH4Cl (35 mL), and the separated aqueous layer was extracted with Et2O (3 50 mL). The combined organic extracts were dried (MgSO4), filtered, concentrated under reduced pressure, and chromatographed (hexanes/EtOAc 100:15) to give 88 as a colorless oil; yield: 6.58 g (90%).
4.4.17.5.2
4-(tert-Butyldiphenylsiloxy)butan-1-ol (88):[89]
Method 2: Silylation of Alcohols with tert-Butyldiphenylsilyl Trifluoromethanesulfonate
The more reactive tert-butyldiphenylsilyl trifluoromethanesulfonate (TBDPSOTf) is used to silylate hindered alcohols that will not react with tert-butyldiphenylsilyl chloride. An example is silylation of the breynolide intermediate 89 to give ether 90 (Scheme 44).[90] As with other silyl triflates, this reagent is commonly used with 2,6-lutidine in dichloromethane.
Scheme 44 Silylation with tert-Butyldiphenylsilyl Trifluoromethanesulfonate[90]
CO2Me
TBDPSOTf, 2,6-lut CH2Cl2, 0 oC to rt 94%
CO2Me
HO
OMEM
TBDPSO
OMEM
89
90
A soln of alcohol 89 (1.01 g, 3.16 mmol) in CH2Cl2 (25 mL) was cooled to 0 8C and treated with 2,6-lutidine (3.65 mL, 31.6 mmol) and TBDPSOTf (2.45 g, 6.32 mmol). The mixture was stirred at 0 8C for 30 min and at rt for 2 h, and then was quenched with sat. NaHCO3 soln. After the addition of CH2Cl2 (100 mL), the pH of the aqueous phase was adjusted to ca. 7.0 with 1 M HCl. The aqueous phase was extracted with CH2Cl2 (3 150 mL), and the combined organic phases were dried (K2CO3), filtered, and concentrated in vacuo. Flash chromatography (EtOAc/hexanes 2:8) afforded silyl ether 90 as a clear, colorless oil; yield: 1.66 g (94%).
4.4.17.5.3
Methyl (3R,3aR,6S,7S,7aS)-3-(tert-Butyldiphenylsiloxy)-7-[(2-methoxyethoxy)methoxy]octahydrobenzo[b]thiophene-6-carboxylate (90):[90]
Method 3: Migration of a tert-Butyldiphenylsilyl Group to an Alcohol
Although the tert-butyldiphenylsilyl group is considered to be less prone to migration than the tert-butyldimethylsilyl group (Section 4.4.17.3.3)[91] and other silyl derivatives, it can migrate to a hydroxy substituent under basic conditions. Migration of this silyl group
b
404
can occur from a carbon atom or from oxygen. Thus, while it is usually very difficult to silylate a tertiary alcohol with tert-butyldiphenylsilyl chloride or trifluoromethanesulfonate, intramolecular rearrangement of a hydroxylated tert-butyldiphenylsilane can provide a means of accomplishing this protection. An example of tert-butyldiphenylsilyl migration is seen in the rearrangement of hydroxylated silane 91 to silyl ether 92 mediated by 1,8-diazabicyclo[5.4.0]undec-7-ene as the base (Scheme 45).[92]
Scheme 45 Rearrangement of a Hydroxylated tert-Butyldiphenylsilane to a tert-Butyldiphenylsilyl Ether[92]
O OAc
DBU, CH2Cl2 rt, 6 h 90%
OAc
OAc
OAc
TBDPS
OH
OTBDPS
91
92
The severe steric crowding that attends a tertiary tert-butyldiphenylsilyl ether such as 92 may prompt migration of the silyl residue to a less congested site, if one is available. For example, exposure of 93 to sodium hydroxide is sufficient to cause an internal rearrangement of the tertiary silyl ether to yield the secondary tert-butyldiphenylsilyl ether 94 (Scheme 46);[92] the primary tert-butyldimethylsilyl ether remained unaffected under these reaction conditions.
Scheme 46 Rearrangement of a Tertiary tert-Butyldiphenylsilyl Ether to a Secondary tert-Butyldiphenylsilyl Ether[92]
OH OAc
NaOH, t-BuOH H2O, rt, 3 h 70%
TBDPSO
OAc
OTBDMS
OTBDMS
OTBDPS 93
OH
94
To a soln of enone 91 (150 mg, 0.31 mmol) in CH2Cl2 (0.5 mL) at rt was added DBU (10 mg). The mixture was stirred for 6 h and then quenched with aq NH4Cl and extracted with Et2O. The ethereal layer was washed with brine and dried (MgSO4). After removal of solvent under reduced pressure, the residue was chromatographed (silica gel, Et2O/hexanes 1:10) to afford enone 92 as a clear oil; yield: 135 mg (90%).
(2R,3S,4S,5R)-2-Acetoxy-1-(tert-butyldimethylsiloxy)-4-(tert-butyldiphenylsiloxy)-5,6epoxy-3-methylhexan-3-ol (94):[92]
(4S,5R)-5,6-Diacetoxy-4-(tert-butyldiphenylsiloxy)-4-methylhex-1-en-3-one (92):[92]
A soln of epoxide 93 (200 mg, 0.35 mmol) in 1 M NaOH/t-BuOH (1:6, 1.0 mL) was stirred at rt for 3 h. The mixture was quenched with aq NH4Cl and extracted with Et2O. The ethereal layer was dried (MgSO4) and concentrated. The residue was chromatographed (silica gel, Et2O/hexanes 1:4) to afford tertiary alcohol 94 as a clear oil; yield: 140 mg (70%).
Cleavage
4.4.17.5.4
Method 4: Cleavage of tert-Butyldiphenylsilyl Ethers with Tetrabutylammonium Fluoride
In common with other silyl ethers, tert-butyldiphenylsilyl ethers are readily cleaved with tetrabutylammonium fluoride in tetrahydrofuran.[93] The reagent shows no selectivity for tert-butyldiphenylsilyl ethers in different structural environments. For example, the final step in a synthesis of (+)-isobretonin A (96) involves deprotection of both the phenolic and the secondary tert-butyldiphenylsilyl ether of 95 with tetrabutylammonium fluoride (Scheme 47).[94]
b
4.4.17
Silyl Ethers
405
Scheme 47 Fluoride[94]
TBDPSO
Cleavage of a Bis(tert-butyldiphenylsilyl ether) with Tetrabutylammonium

TBAF, THF 0 oC to rt, 12 h 83%
OTBDPS O
95
HO
OH
96
A tert-butyldiphenylsilyl ether is more susceptible to attack by fluoride ion than a triisopropylsilyl ether, a property that can be attributed to electron withdrawal by the phenyl substituents on silicon. This distinction is manifested, for example, in the selective cleavage of the tert-butyldiphenylsilyl ether of 97, yielding alcohol 98 in which the triisopropylsilyl ether is left intact (Scheme 48).[65]
Scheme 48 Fluoride[65] Cleavage of a tert-Butyldiphenylsilyl Ether with Tetrabutylammonium
TBAF, THF rt, 4 d 68%
TIPSO
CO2H TBDPSO 97
Pri
TIPSO
CO2H
HO
Pri
98
To a soln of bis(silyl ether) 95 (190 mg, 0.2 mmol) in THF (20 mL) at 0 8C under argon was added 1 M TBAF in THF (0.5 mL, 0.5 mmol). The mixture was allowed to reach rt and was stirred for 12 h. The reaction was then quenched with silica gel (2 g) and the soln was concentrated. The mixture was dissolved in CH2Cl2 (1 mL) and purified by column chromatography (silica gel, EtOAc/hexane 1:3) to give isobretonin A (96); yield: 68.38 mg (83%).
(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 Acid (98):[65]
(+)-Isobretonin A (96):[94]
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 THF (5.0 mL). The resulting soln was stirred for 3 d at rt, and more TBAF soln (0.12 mL, 0.12 mmol) was added. Following an additional 1 d of stirring, the soln was concentrated
b
406
in vacuo and purified by column chromatography (silica gel, 2550% EtOAc/hexanes, then 1030% MeOH/hexanes) to provide hydroxy acid 98 as a white foam; yield: 0.123 g (68%).
4.4.17.5.5
Method 5: Cleavage of tert-Butyldiphenylsilyl Ethers with Tetrabutylammonium Fluoride in Acetic Acid
Acetic acid may be used as a buffer in the cleavage of tert-butyldiphenylsilyl ethers with tetrabutylammonium fluoride in tetrahydrofuran.[95] This valuable technique moderates the basicity that accompanies this source of fluoride ion and which can sometimes lead to destruction of base-sensitive substrates. An application of this method is seen in the final step of a synthesis of (+)-acutiphycin (100), where a tert-butyldiphenylsilyl ether is smoothly removed from 99 (Scheme 49).[96] An attempt to unmask this ether with unbuffered tetrabutylammonium fluoride led to decomposition.
Scheme 49 Cleavage of a tert-Butyldiphenylsilyl Ether with Tetrabutylammonium Fluoride in the Presence of Acetic Acid[96]
OTBDPS OH
O OH H O
TBAF, AcOH THF, rt, 42 h 95%
O OH H O
OH
OH
99
100
(+)-Acutiphycin (100):[96]
A stock soln was prepared by addition of AcOH (0.15 mL) to a soln of 1.0 M TBAF in THF (2.5 mL). Silyl ether (+)-99 (6.0 mg, 8.7 mol) was dissolved in THF (3.3 mL) and treated with a portion of the stock soln (1.5 mL). After 42 h at rt, the mixture was diluted with EtOAc (25 mL), washed with sat. aq NaHCO3 (2 15 mL) and brine (15 mL), dried (MgSO4), filtered, and concentrated. Flash chromatography (hexane/EtOAc 2:1) afforded (+)-100 as a colorless, amorphous solid; yield: 3.8 mg (95%).
4.4.17.5.6
Method 6: Cleavage of tert-Butyldiphenylsilyl Ethers with Tris(dimethylamino)sulfur (Trimethylsilyl)difluoride
The mild fluoride source tris(dimethylamino)sulfur (trimethylsilyl)difluoride (TASF)[59] can be employed to cleave a tert-butyldiphenylsilyl ether in the presence of certain other silyl ethers, including a tert-butyldimethylsilyl ether. This valuable selectivity arises from the increased propensity of a silicon atom to suffer nucleophilic attack when it carries aryl substituents as compared to alkyl groups. A demonstration of the unique selectivity of tris(dimethylamino)sulfur (trimethylsilyl)difluoride has been provided in the conversion of the bis(silyl ether) 101 into alcohol 102 (Scheme 50).[97]
b
4.4.17
Silyl Ethers
407
Scheme 50 Selective Cleavage of a tert-Butyldiphenylsilyl Ether with Tris(dimethylamino)sulfur (Trimethylsilyl)difluoride[97]

TBDPSO HO
TASF (1.2 equiv) DMF, 0 oC to rt 84%
TBDMSO
TBDMSO
But
But
101
102
To a 0 8C soln of bis(silyl ether) 101 (57 mg, 0.080 mmol) in DMF (0.500 mL) was added 1.30 M TASF in DMF (0.073 mL, 0.095 mmol). The reaction was stirred at 0 8C for 2 h, then warmed to rt for 2 h. The mixture was diluted with EtOAc and washed with pH 7 buffer. The aqueous layer was extracted with EtOAc (3 10 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The crude oil was purified by chromatography (silica gel, Et2O/hexanes 1:1) to give 102; yield: 32 mg (84%).
4.4.17.5.7
(2R,5S,6S,9R)-2-tert-Butyl-6-[(1E,3S)-3-(tert-butyldimethylsiloxy)-2-methylhexa-1,5-dienyl]8-(hydroxymethyl)-9-methyl-1,3-dioxaspiro[4.5]dec-7-en-4-one (102):[97]
Method 7: Cleavage of tert-Butyldiphenylsilyl Ethers with Hydrogen FluoridePyridine Complex
Hydrogen fluoridepyridine complex in tetrahydrofuran[98] and hydrogen fluoride in aqueous acetonitrile[99] are effective reagents for unmasking a tert-butyldiphenylsilyl ether. They are relatively unselective but are valuable for cleaving a tert-butyldiphenylsilyl ether where basic conditions (e.g., see Section 4.4.17.5.5) cannot be employed. An application of the hydrogen fluoridepyridine reagent is seen in the deprotection of the tertbutyldiphenylsilyl ether 103 to give alcohol 104 (Scheme 51), an intermediate in a route to (+)-acetoxycrenulide.[100]
Scheme 51 Cleavage of a tert-Butyldiphenylsilyl Ether with Hydrogen FluoridePyridine Complex[100]
O H H O H
HFpy MeCN, H2O, 6 h 85%
TBDPSO
HO
H OAc
H OAc
103
104
A soln of silyl ether 103 (153 mg, 0.27 mmol) in MeCN (8 mL) was treated with HFpy soln [prepared by adding 48% HF (1 mL) to a mixture of MeCN (1 mL) and pyridine (2.4 mL) at 0 8C] in three equal aliquots (0.33 mL each) over 6 h. The mixture was then diluted with H2O and extracted with EtOAc. The combined organic extracts were washed with 5% HCl, sat. NaHCO3 soln, and brine prior to drying and solvent evaporation. Chromatography of the residual gel (EtOAc/hexanes 9:1) afforded alcohol 104 as a colorless oil; yield: 77 mg (85%).
(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 (104):[100]
b
408
4.4.17.5.7.1
Variation 1: Cleavage with Hydrogen FluorideTriethylamine Complex
The use of triethylamine in place of pyridine with hydrogen fluoride renders the fluoride ion a potent nucleophile while suppressing side reactions that occasionally result from acid catalysis by hydrogen fluoridepyridine complex. The hydrogen fluoridetriethylamine system in acetonitrile as the solvent is particularly useful for cleaving tert-butyldiphenylsilyl ethers in structures that contain acid-sensitive functional groups. The deprotection of tert-butyldiphenylsilyl ether 105, which bears numerous appendages that would be susceptible to acidic hydrolysis, illustrates an application of this reagent (Scheme 52). The resultant primary alcohol 106 was a key intermediate in a synthesis of (+)-damavaricin D.[101]
Scheme 52 Cleavage of a tert-Butyldiphenylsilyl Ether with Hydrogen FluorideTriethylamine Complex[101]
O OMOM O
SiMe3
MOMO
OMOM
Et3NHF, MeCN, reflux, 12 h 89%
OAc
OAc O
OTBDPS
105
OMOM O
SiMe3
MOMO
OMOM
OAc
OAc O
OH
106
A soln of silyl ether 105 (0.70 g, 0.53 mmol) and Et3NHF (250 mg, 2.1 mmol) in MeCN (6.0 mL) was heated at reflux for 12 h. The soln was allowed to cool to 23 8C then partitioned between Et2O (400 mL) and H2O (150 mL). The organic phase was washed with NaHCO3 soln (50 mL) and H2O (50 mL), dried (MgSO4), filtered, and concentrated, which afforded a yellow oil. Purification of the crude product by flash chromatography (EtOAc/hexanes 3:7) gave the alcohol 106 as a ca. 1:1 mixture of atropisomers (white foam); yield: 0.51 g (89%).
2-(Trimethylsilyl)ethyl 8-Allyloxy-5-[(2E,4S,5S,6R,7R,8R,9R,10R,11R,12R)-5,7-diacetoxy-8(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 (106):[101]
b
4.4.17
Silyl Ethers
409
4.4.17.6
Other Silyl Ethers
The need for selectivity in the protection of alcohols has brought forth a suite of silylating agents bearing a variety of substituents at the silicon atom that extend beyond the structural types described in Sections 4.4.17.14.4.17.5. Silyl ethers prepared with these reagents possess reactivity toward cleavage which varies widely and which can be tuned to particular applications. The combination of steric and electronic effects of substituents at silicon in these silyl ethers leads to properties that are often difficult to predict, and most of the information about silyl ethers in this group has been obtained from empirical observation. Although ethers in this group have been less extensively exploited in synthesis than the silyl ethers described in the foregoing sections, specific examples suggest that they can play a valuable role in the differential protection of alcohols during a complex synthesis, and may find more general application as their reactivity becomes better understood. All of the silyl ethers in this group can be prepared by one or more of the methods described for silyl ethers in Sections 4.4.17.14.4.17.5, the most frequently used method being reaction of an alcohol with either the silyl chloride, bromide or triflate. The subtle but real variation in the behavior of these silyl ethers towards cleavage reagents forms the basis for their utility as specific protection devices for alcohols. Thus, diethylisopropylsilyl ethers are more stable than triethylsilyl ethers, but are more easily cleaved than tert-butyldimethylsilyl ethers. Conditions have been described that result in retention of a secondary tert-butyldimethylsilyl ether while removing a diethylisopropylsilyl ether.[101] As an operational principle, a diethylisopropylsilyl ether is considered to be approximately 90 times more stable than a trimethylsilyl ether towards acidic hydrolysis and 600 times more resistant than a trimethylsilyl ether towards cleavage with fluoride ion. An isopropyldimethylsilyl ether[102] is even more labile towards acidic hydrolysis than a diethylisopropylsilyl ether, and is cleaved rapidly in aqueous acetic acid at room temperature.[103] Other hydroxy protecting groups, such as a tetrahydropyranyl ether, will survive conditions that typically cleave an isopropyldimethylsilyl ether. Triphenylsilyl ethers are usually prepared from the corresponding silyl chloride,[104] and are quite labile towards basic hydrolysis. They are approximately 400 times less reactive towards acidic cleavage than trimethylsilyl ethers. Methyldiphenylsilyl ethers[105] are intermediate in stability between trimethylsilyl and triethylsilyl ethers. Unlike most trimethylsilyl ethers, they will survive chromatography on silica gel, but a serious limitation is that they do not withstand many of the common reagents used in synthesis, including acids, bases, reducing agents, and oxidants. tert-Butylmethoxyphenylsilyl ethers provide protection for alcohols where selectivity is desired in the presence of other silyl ethers, especially tert-butyldimethylsilyl or tertbutyldiphenylsilyl ethers.[106] The tert-butylmethoxyphenylsilyl ether is appreciably more stable towards acidic hydrolysis than a tert-butyldimethylsilyl ether. On the other hand, a tert-butylmethoxyphenylsilyl ether is cleaved more readily with fluoride than either a tert-butyldimethylsilyl or a tert-butyldiphenylsilyl ether, allowing for removal of the former in the presence of the latter two classes of ethers.[107] Primary, secondary, and tertiary alcohols can be converted quite readily into their tert-butylmethoxyphenylsilyl ethers, but the fact that the silicon atom in this class of ethers is stereogenic will result in diastereomers if the parent alcohol is chiral. Tris(trimethylsilyl)silyl (sisyl) ethers are among the most stable of the silyl ethers.[108] Readily prepared by reaction of an alcohol with tris(trimethylsilyl)silyl chloride in the presence of 4-(dimethylamino)pyridine, these ethers withstand strongly acidic conditions that will cleave most other silyl ethers. Tris(trimethylsilyl)silyl ethers are cleaved with tetrabutylammonium fluoride, however, and they can be cleanly removed by photolysis in methanol.
b
410
tert-Butoxydiphenylsilyl ethers possess stability towards acidic hydrolysis that is comparable to that of tert-butylmethoxyphenylsilyl ethers.[109] Like the latter group, they are also quite labile towards fluoride. An advantage of the tert-butoxydiphenylsilyl group over the tert-butylmethoxyphenylsilyl residue is that it is achiral and, hence, does not produce diastereomeric silyl ethers.
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Sily L Protecting Groups

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FOR PERSONAL USE ONLY

Product Subclass 17: Silyl Ethers

J. D. White and R. G. Carter

FOR PERSONAL USE ONLY

Method 1: Silylation of Alcohols with Chlorotrimethylsilane

FOR PERSONAL USE ONLY

Scheme 1 Silylation with Chlorotrimethylsilane[23]

Method 2: Silylation of Alcohols with Trimethylsilyl Trifluoromethanesulfonate

Method 3: Silylation of Alcohols with Trimethylsilyl Cyanide

for references see p 410

FOR PERSONAL USE ONLY

AcOH, H2O, THF 99%

Methyl 11-(tert-Butoxycarbonyloxy)-13-(2-hydroxyethylidene)-1-(triethylsiloxy)-8(trimethylsiloxy)bicyclo[7.3.1]trideca-4,9,11-triene-2,6-diyn-10-ylcarbamate (7):[27]

Method 4: Silylation of Alcohols with N,O-Bis(trimethylsilyl)acetamide

N,O-Bis(trimethylsilyl)acetamide (BSA) is a relatively unselective reagent that can convert

FOR PERSONAL USE ONLY

Scheme 4 Silylation with N,O-Bis(trimethylsilyl)acetamide[30]

BSA, THF, 90 oC, 1 h 92%

Methyl (2E,4S,5R)-4-Acetoxy-2-(acetylamino)-5-[(2S)-1-(benzyloxycarbonyl)aziridin-2-yl]-3bromo-5-(trimethylsiloxy)pent-2-enoate (9):[30]

Method 5: Cleavage of Trimethylsilyl Ethers with Acidic Reagents

PPTS, MeOH rt, 30 min 94%

HCl, MeOH, CH2Cl2 0 oC, 30 min 90%

for references see p 410

FOR PERSONAL USE ONLY

Method 6: Cleavage of Trimethylsilyl Ethers under Basic Conditions

K2CO3, MeOH 0 oC, 1.5 h 96%

FOR PERSONAL USE ONLY

Scheme 8 Cleavage of a Trimethylsilyl Ether with Tetrabutylammonium Fluoride[34]

TBAF, THF, 0 oC 98%

Method 1: Silylation of Alcohols with Chlorotriethylsilane

for references see p 410

FOR PERSONAL USE ONLY

Variation 1: With Chlorotriethylsilane in Pyridine

TESCl, py, rt, 22 h 82%

FOR PERSONAL USE ONLY

Tri-tert-butyl {1S-[1,3,4,5,6(2E,4S,6S),7]}-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 (21):[38]

Variation 2: With Chlorotriethylsilane in the Presence of 4-(Dimethylamino)pyridine

for references see p 410

FOR PERSONAL USE ONLY

Method 2: Silylation of Alcohols with Triethylsilyl Trifluoromethanesulfonate

Silylation with Triethylsilyl Trifluoromethanesulfonate[41]

Method 3: Cleavage of Triethylsilyl Ethers under Acidic Conditions

FOR PERSONAL USE ONLY

Cleavage of a Triethylsilyl Ether with Hydrogen FluoridePyridine Complex[41]

HFpy, py, THF, 0 oC 95%

Variation 1: In the Presence of 4-Toluenesulfonic Acid

for references see p 410

FOR PERSONAL USE ONLY

Variation 2: With Trifluoromethanesulfonic Acid

TfOH, H2O, THF, rt 95%

Method 4: Cleavage of Triethylsilyl Ethers with Tetrabutylammonium Fluoride

FOR PERSONAL USE ONLY

Cleavage of Triethylsilyl Ethers with Tetrabutylammonium Fluoride[45]

TBAF, THF, 0 oC, 45 min 94%

Method 1: Silylation of Alcohols with tert-Butyldimethylsilyl Chloride

for references see p 410

FOR PERSONAL USE ONLY

Variation 1: In the Presence of 4-(Dimethylamino)pyridine

TBDMSCl, DMAP DMF, 21 oC, 3 d 81%

FOR PERSONAL USE ONLY

Methyl (3S)-4-(tert-Butyldimethylsiloxy)-3-hydroxybutanoate (39):[50]

rac-[1(5S,6S,8R,9R),2,4a,5,8a]-6-(Hydroxymethyl)-4-methoxy-9-methyl-2-oxo-8[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 (59):[63]