Ether tetrahydropyranyl

Six protective groups for alcohols, which may be removed successively and selectively, have been listed by E.J. Corey (1972B). A hypothetical hexahydroxy compound with hydroxy groups 1 to 6 protected as (1) acetate, (2) 2,2,2-trichloroethyl carbonate, (3) benzyl ether, (4) dimethyl-t-butylsilyl ether, (5) 2-tetrahydropyranyl ether, and (6) methyl ether may be unmasked in that order by the reagents (1) KjCO, or NH, in CHjOH, (2) Zn in CHjOH or AcOH, (3) over Pd, (4) F", (5) wet acetic acid, and (6) BBrj. The groups may also be exposed to the same reagents in the order A 5, 2, 1, 3, 6. The (4-methoxyphenyl)methyl group (=MPM = p-methoxybenzyl, PMB) can be oxidized to a benzaldehyde derivative and thereby be removed at room temperature under neutral conditions (Y- Oikawa, 1982 R. Johansson, 1984 T. Fukuyama, 1985). 

The tetrahydropyranyl ether, prepared from a phenol and dihydropyran (HCl/ EtOAc, 25°, 24 h), is cleaved by aqueous oxalic acid (MeOH, 50-90°, 1-2 h). ... 

The cyclohexylidene ketal, prepared from a catechol and cyclohexanone (AI2O3/ TsOH, CH2CI2, reflux, 36 h), is stable to metalation conditions (RX/BuLi) that cleave aiyl methyl ethers. The ketal is cleaved by acidic hydrolysis (coned. HCl/ EtOH, reflux, 1.5 h, 20°, 12 h) it is stable to milder acidic hydrolysis that cleaves tetrahydropyranyl ethers (1 AHCl/EtOH, reflux, 5 h, 91% yield). ... 

The /-propyldimethylsilyl ester is prepared from a carboxylic acid and the silyl chloride (Et3N, 0°). It is cleaved at pH 4.5 by conditions that do not cleave a tetrahydropyranyl ether (HOAc-NaOAc, acetone-H20, 0°, 45 min - 25°, 30 min, 91% yield). ... 

In the latter case, one end of the glycol is protected as its tetrahydropyranyl ether. Upon hydrolysis, a two-armed crown is revealed which may then be treated with the bis-crown precursor identified above. The result will be a tris-crown system and the approach is illustrated below in Eq. (3.35). 

The principal variations on the normal crown synthesis methods were applied in preparing mixed crowns such as those shown in Eq. (3.55) and in forming isomers of the dibinaphthyl-22-crown-6 systems. The latter has been discussed in Sect. 3.5 (see Eq. 3.21) . The binaphthyl unit was prepared to receive a non-naphthyl unit as shown in Eq. (3.57). Binaphthol was allowed to react with the tetrahydropyranyl ether or 2-chloroethoxyethanol. Cleavage of the THP protecting group followed by tosyla-tion of the free hydroxyl afforded a two-armed binaphthyl unit which could serve as an electrophile in the cyclization with catechol. Obviously, the reaction could be accomplished in the opposite direction, beginning with catechol". ... 

When 16-dehydropregnenolone itself is reduced, less than 3 % of the starting material remains unreduced and reduction of the tetrahydropyranyl ether of 16-dehydropregnenolone (70) in the presence of one mole of t-butyl alcohol is also virtually complete. In both cases, however, crystallization of the crude products gives only modest yields of pure products. 

In striking contrast to the above observations is the finding that both reduction and reductive methylation of the tetrahydropyranyl ether of 17a-ace-toxypregnenolone (71) afford the expected products (72a, b) in 85-88 % yields by direct crystallization of the crude reaction products. Clearly, the complications in the reduction of the 16-en-20-one system are attributable primarily to reactions of the carbon-carbon double bond rather than to the a-carbanion (73), which is the final intermediate in both the reduction of the 16-dehydro compounds and the 17-acetoxy ketones. 

Enol ethers (15) and mixed acetals (16) are readily obtained from secondary but not from tertiary alcohols, whereas tetrahydropyranyl ethers can be formed even from tertiary alcohols. This is a result of the greater steric requirements of the reagents (17) and (18) as compared to (19). 

Tetrahydropyranyl ethers are prepared by reaction with 2,3-dihydropyran, and a catalyst such as hydrochloric acid, " phosphorous oxychloride or p-toluenesulfonic acid at room temperature. 3iS-Hydroxy-5-enes " also form pyranyl ethers by distillation of a solution of the steroid and dihy-dropyran in ether without a catalyst. 

Crude tetrahydropyranyl ethers are usually a mixture of epimers due to formation of an additional asymmetric center. Consequently these derivatives are sometimes difficult to characterize. 

Beta- and 3a-alcohols of the 5)5- and 5a-series respectively also form tetrahydropyranyl ethers, cycloalkenyl ethers and mixed acetals. ... 

Tetrahydropyranyl ethers have been prepared from the quasi-axial 7a-hydroxyl in a 3)5-acetoxy-A -7a-ol, but in this case enhanced reactivity is due to the adjacent double bond. °... 

The 1 la-hydroxyl group is normally reactive and protection as tetrahydropyranyl ether is feasible. 

The tertiary 17) -hydroxyl group does not form bulky enol ethers and mixed acetals. However, tetrahydropyranyl ethers are obtained from 17a-ethynyl-17]3-hydroxy compounds. Tetrahydropyranyl ethers have also been prepared from tertiary 17a-hydroxyl groups. ... 

Unhindered 20oc- and 20) -hydroxyl groups can be protected as tetrahydropyranyl ethers. 

The 21-hydroxyl group in the corticosteroid series can be protected as the base stable triphenylmethyl ether and tetrahydropyranyl ether. " " Mixed acetals from 21-alcohols are extremely acid sensitive compounds. ... 

Lithium reductive deacetoxylation of the tetrahydropyranyl ether of 17o -ace-toxypregn-5-en-3/3-ol-20-one, 56... 

Many functional groups are stable to alkaline hydrogen peroxide. Acetate esters are usually hydrolyzed under the reaction conditions although methods have been developed to prevent hydrolysis.For the preparation of the 4,5-oxiranes of desoxycorticosterone, hydrocortisone, and cortisone, the alkali-sensitive ketol side chains must be protected with a base-resistant group, e.g., the tetrahydropyranyl ether or the ethylene ketal derivative. Sodium carbonate has been used successfully as a base with unprotected ketol side chains, but it should be noted that some ketols are sensitive to sodium carbonate in the absence of hydrogen peroxide. The spiroketal side chain of the sapogenins is stable to the basic reaction conditions. 

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