Ethers protection

Historically, simple Vz-alkyl ethers formed from a phenol and a halide or sulfate were cleaved under rather drastic conditions (e.g., refluxing HBr). New ether protective groups have been developed that are removed under much milder conditions (e.g., via nucleophilic displacement, hydrogenolysis of benzyl ethers, and mild acid hydrolysis of acetal-type ethers) that seldom affect other functional groups in a molecule. 

Tetrabutylammonium fluoride (TBAF) is usually used in the form of the trihydrate or as a solution in tetrahydrofuran (THF). The pure form is difficult to isolate, owing to decomposition to FFF, tributylamine, and but-l-ene [18, 19] on dehydration. It has been used for a variety of reactions, including as a catalyst for various reactions with silicon compounds [20, 21]. One of its main uses is in the cleavage of silyl ether protecting groups [22]. 

Broxton and Roper measured the rate of dissociation (A 3) of the (ii)-diazo ether, A 2, and the rate of the protection reaction (A p), i.e., the transformation of the (Z)-into the (ii)-ether ( protection because the diazo ether is protected against dediazoniation almost completely if present as the ( >isomer). Rate constants kx and k are known from Ritchie and Virtanen s work (1972). The results demonstrate firstly that the initial reaction of the diazonium ion takes place in such a way that almost exclusively the (Z)-ether is formed directly (ki/k3 = 120). The protection rate constant kp is a simple function of the intrinsic rate constants as shown in Scheme 6-4. 

OH must help subsequent isomerization, because ( )-30 is stable in the presence of 1, even after 2 d at 70°C. To test whether the bulk of the silyl ether protecting group was responsible for this reactivity difference, compound 32 was allowed to isomerize, forming a high yield of (ii)-33 at room temperature. In this case, heating at 70°C for 15 h does seem to lead to traces of what is tentatively identified as 34, but the second isomerization is clearly much slower than the first. Further studies are planned to elucidate the role of a hydroxyl substituent in alkene isomerization... 

Selective removal of the benzyl ether-protecting group without hydrogenolysis of the ketal C-O bonds was performed on Ra-Ni in EtOH.154 155 A solution of benzyloxy acetal in MeOH with 5% Pd/C was stirred at room temperature with a H2 pressure from a balloon until the reaction was complete (Scheme 4.30).156... 

In some cases the hydrogenation of the double bond in an unsaturated benzyl ether is necessary without debenzylation. To hydrogenate the carbon-carbon double bond 5% Pd/C in AcOEt was used for 1.5 hours (Scheme 4.40).136 The benzyl ether-protecting group was removed over Pd(OH)2 in AcOEt for 1 hour. 

Selective removal of the benzyl ether-protecting group in compound 9 (Fig. 4.1) was made through both transfer hydrogenolysis and the conventional catalytic hydrogenolysis. 

The hydroxyl group was usually protected, because cyanohydrins have tendency to racemization or even decomposition. Vinyl ethers or acetal and acid catalysts furnish acetals [62]. Trialkylsilyl chlorides and imidazole are used to give silyl ethers [63]. Commonly used protective groups are silyl ether, ester, methoxy isopropyl (MIP) ether, and tetrahydro-pyranyl ether. ( -Protected cyanohydrins are tolerant to a wider range of cyanide/nitrile transformations and are utilized widely in the synthesis of compounds of synthetic relevance in organic chemistry. 

The methoxymethyl ether protecting groups of 33 were then cleaved using triphenylphosphine and carbon tetrabromide. The resulting hydroquinone function was oxidized by palladium on carbon under an atmosphere of air to afford the quinone 52 (70 %). A two-step procedure was implemented to install the diazo function. First, the ketone function of 52 was condensed with N,N -bis( tert-butyldimethylsilyl)hydrazine in the presence of scandium triflate, which formed the Af-tert-butyldimethylsilyl hydrazone 53. The hydrazone (53) was then oxidized using difluoroiodobenzene to afford kinamycin C (3) in 35 % yield. 

Our retrosynthesis of (—)-kinamycin F (6) is shown in Scheme 3.20 [45]. It was envisioned that (—)-kinamycin F (6) could be prepared from the protected diazofluorene 114 by conversion of the ketone function of 114 to a trans-], 2-diol, followed by deprotection of the acetonide and methoxymethyl ether protecting groups. The diazofluorene 114 was envisioned to arise from diazo transfer to the hydroxyfulvene 115. The cyclopentadiene substructure of 115 was deconstructed by a two-step annulation sequence, to provide the bromoquinone 116 and the p-trimethylsilylmethyl unsaturated ketone 117. The latter two intermediates were prepared from juglone (118) and the silyl ether 119, respectively. 

A tandem enolate-arylation-allylic cyclisation, in which an essential z-butyldimethylsilyl ether protecting group delays the cyclisation step until the Pd-catalysed arylation is complete, enables 1-vinyl-l//-[2]benzopyrans 54 to be prepared from 2-bromobenzaldehyde (Scheme 32) <00CC1675>. 4-Substituted isochromans 55 are formed from aldehydes by a Pd-catalysed termolecular queuing cascade. The sequence involves cyclisation of an aryl iodide onto a proximate alkyne followed by an allene insertion. Transmetallation with indium then allows addition to the aldehyde (Scheme 33) . 

Recognizing that l-(phenylsulfonyl)-3-lithioindole tends to isomerize to the corresponding 2-lithioindole derivative, Bosch et al. used a silyl ether protection to solve the problem. They prepared 3-indolylzinc reagent 36 from 3-bromo-l-(terr-butyldimethylsilyI)indole (35) and then coupled 36 with 2-halopyridine 33 to form 3-(2-pyridyl)indole 37. Finally, the Negishi adduct 37 was further manipulated to a naturally occurring indole alkaloid, ( )-nordasycarpidone (38) [23,27]. 

Scheme 16 Intramolecular aglycon delivery approach using NAP ether protected glycosyl donors.

The thermal stability of silyl ethers (protected hydroxyl functions) is good. Hydrolytically, silylethers are less stable but the rate of hydrolysis of R3Si-OR changes with R, /.< ., ter. butyldimethylsilyl ethers hydrolyse about 10,000 times slower than trimethylsilyl ethers. 

Scheme 27 Oxidative cleavage of the benzyl ether-protecting group.

The effects observed for the ether-protected carbohydrates are likely a result of their lower degree of positive charge destabilization than the corresponding ester groups, leading to side reactions such as ring contraction and ehmination. ... 

A further eight steps were required to convert the cyclopentanone 52 into the sulfone 59 that was deprotonated and treated with an allylic bromide (60) to afford the alkylated sulfone 61 (Scheme 7). The sulfone moiety and the benzyl ether protecting group were reductively removed in a one-pot procedure to afford a mono-protected diol (62). 

---