Hydroxy ethers formation

Addition of a hydroxy group to alkynes to form enol ethers is possible with Pd(II). Enol ether formation and its hydrolysis mean the hydration of alkynes to ketones. The 5-hydroxyalkyne 249 was converted into the cyclic enol ether 250[124], Stereoselective enol ether formation was applied to the synthesis of prostacyclin[131]. Treatment of the 4-alkynol 251 with a stoichiometric amount of PdCl2, followed by hydrogenolysis with formic acid, gives the cyclic enol ether 253. Alkoxypalladation to give 252 is trans addition, because the Z E ratio of the alkene 253 was 33 1. 

Steroidal 17-cyanohydrins are relatively stable towards chromium trioxide in acetic acid (thus permitting oxidation of a 3-hydroxyl group ) and towards ethyl orthoformate in ethanolic hydrogen chloride (thus permitting enol ether formation of a 3-keto-A system ). Sodium and K-propanol reduction produces the 17j -hydroxy steroid, presumably by formation of the 17-ketone prior to reduction. ... 

With 11/3-hydroxy steroids, 11/3, 19-ether formation competes with hemi-acetal formation.This is a consequence of steric hindrance of the 11/5-oxygen by the C-18 and C-19 iodomethyl groups which reduces the rate of hypoiodite formation [(3) (5)] even though the conformation of the... 

Sections D through H of Scheme 3.2 involve oxygen nucleophiles. The hydrolysis reactions in Entries 12 and 13 both involve benzylic positions. The reaction site in Entry 13 is further activated by the ERG substituents on the ring. Entries 14 to 17 are examples of base-catalyzed ether formation. The selectivity of the reaction in Entry 17 for the meta-hydroxy group is an example of a fairly common observation in aromatic systems. The ortho-hydroxy group is more acidic and probably also stabilized by chelation, making it less reactive. 

EGA-catalyzed ring opening of epoxides, (14), is one of the most-studied catalytic EGA reactions. The proper choice of solvent and supporting electrolyte allows selective formation of a ketone, an allylic alcohol, an acetonide, or an a-hydroxy ether. Scheme 7. 

Nicolaou hydroxy-ketone reductive cyclic ether formation... 

Finally, it should be pointed out that in some cases epoxides are opened by a remote hydroxy group within the molecule to give the five-membered ethers [41]. We are currently investigating how the conformation of an open chain epoxy polyol might be responsible for cyclic ether formation [43]. 

Details of the Janda-Chen synthesis were as follows. A tetrahydropyran (THP) linker was attached to the NCPS support enabling attachment of alcohols via THP ether formation.13 The THP-NCPS resin 1 is derivatized with / -(+)-4-hydroxy-2-cyclopentanone 2, giving the THP ether-based resin 3, followed by coupling of the C13 20 fragment by enone-cuprate addition. The cuprate required was generated from the corresponding E-vinyl stannane 4. The resulting enolate was trapped as the silyl end ether... 

The rate constants for the reactions between OH and a range of ethers and hydroxy ethers have been reported at 298 K233 as well as those for reactions between dimethyl ether and methyl f-butyl ether over the range 295-750 K.234 Data from the former study show deviations from simple structure-activity relationships which were postulated to arise due to H-bonding in the reaction transition states.233 The atmospheric lifetime of methyl ethyl ether has been determined to be approximately 2 days.235 Theoretical studies on the H-abstraction from propan-2-ol (a model for deoxyribose) by OH have been reported using ab initio methods (MP2/6-31G ).236 The temperature dependence (233-272 K) of the rate coefficients for the reaction of OH with methyl, ethyl, n-propyl, n-butyl, and f-butyl formate has been measured and structure-activity... 

Schotten-Baumann type N-benzoylation was carried out on trans-4-hydroxy-L-proline 34,39 giving amide 43 in a satisfactory yield of 65%. The disappointing yield here could be attributed to difficulties experienced in recrystallization of the product 43. The amide 43 was esterified to give tert-butyl ester 44 using a modification of a procedure described by Widmer40 with dimethylformamide-dineopentyl acetal and tert-butanol as reagents. This provided crystalline 44 in 71% yield from 43 with no evidence of terf-butyl ether formation at the C-4 hydroxyl group (Scheme 12). 

Unsaturated ethers, RCH = CHCH20CHj, have been prepared from the corresponding allylic alcohols and dimethyl sulfate in the presence of sodium amide (60-80%). Acetylenic ethers are made in a similar manner from acetylenic alcohols. The hydroxyethylation of phenols with ethylene sulfite or ethylene carbonate appears to be a promising reaction for the formation of hydroxy ethers of the type ROCH,CHjOH. ... 

Ether formation often leads to enhanced oral activity. 17/8-Hydroxy-5a-androstan-3-one 17-(rmethoxy)cyclopentyl ether (D-130), 17)3-hydroxy-5a-androstan-3-one 17-(l -ethoxy)cyclopentyI ether (D-132), 17j3-hydroxy-5a-androst-l-en-3-one 17-(r-ethoxy)cyclopentyl ether (A-163), and 17j3-hydroxy-5a-androst-l-en-3-one 17-cyclopent-r-enyl ether (A-164) are all reported to possess favorable anabolic-androgenic ratios with increased anabolic and androgenic properties. The enhancement of oral activity is interesting in view of the fact that the ether bond of these compounds is easily broken, as manifested by the strongly enhanced excretion of 17-ketosteroids in humans treated with the ether derivatives [144]. 

Transformation of 417b into lactone 419, followed by Mc2CuLi addition, hydroxylation, and oxidation with N-chlorosuccinimide gives the hydroxy lactone 420 (80JOC4820). Enol ether formation, reduction of the lactone and ester functions, and hydrolysis of the enol ether give hydroxy ketone... 

Isomers of 6,7-Epoxy-linalool as Precursors of Linalool Oxides. Previously, the triol (21) had been proposed as a possible precursor of the hydroxy ethers (14) and (15), the so-called linalool oxides(Fig-ure 8). At an acidic pH (<3.5) and/or during heat treatment (e.g., steam distillation/extraction), the triol (21) had been found to be decomposed to (14) and (15) (23,24). In these previous experiments no formation of the corresponding pyranoid linalool oxides (22) and (23) was observed. We evaluated the hypothesis that linalool oxides are formed from triol (21) under natural conditions of papaya pulp (i.e. pH 5.6) and could find no formation of linalool oxides. Even in model experiments carried out at pH 3.5, only traces of linalool oxides were detected after incubation of (21) for three days. As a result of these experiments the isomers of 6,7-epoxy-linalool have to be considered as the natural precursors of linalool oxides (14, 15) as recently suggested by Ohloff et al. (25). The latter s proposal was based on earlier findings obtained in a series of chemical reactions (9). 

Epoxy-linalool (31) has been proposed as the biogenetic precursor of the isomeric hydroxy ethers (21)-(24) as shown in Figure 7 (16). Recently, in our studies of the precursors of papaya fruit volatiles, compound (31) was detected as a natural constituent of this fruit (17). Due to the acidity of the medium (pH 3.5), in the present study, the detection of the labile epoxy derivative (31) was not expected. From the hydroxy ethers (23) and (24), the formation of acetates is easy to understand. 

The remaining segment, C-3 to C-8, was constructed by a similar route. Optically active allylic alcohol 229, produced from lithio ethylacetate and methacrolein followed by a second Sharpless kinetic resolution, was hydrolized to the corresponding hydroxy acid. Neutralization followed by iodolactonization then gave 230 in 85% yield. This highly stereoselective cyclization produced a cis-trans ratio of 20 1 via a one-pot procedure. Deprotonation and methylation afforded the expected anti a-methyl compound, contaminated with about 10% of the syn compound but none of the methyl ether. Formation of the silyl ether then produced 231 in 66% yield. Dibal reduction to the aldehyde concomitant... 

This approach can use the inherent regioselectivity of silyl enol ether formation (chapter 3) using kinetic or thermodynamic enolisation. Hence kinetic enolisation of enones (chapter 11) occurs on the a side leading to 2-Me3SiO-butadienes such as 222. Epoxidation of this silyl enol ether gives the unstable silyloxy ketone 223 which can be desilylated by fluoride ion and hence transformed into the hydroxyketone 225 or acetoxy ketone 224. These transformations are useful because the hydroxy ketones can be unstable34 (see below). 

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