Hemiacetal ethers

The structural features of this group are summarized as follows (1) possession of an acetal or a hemiacetal ether linkage between C-8 and C-10, and (2) either absence of a substituent or presence of a hydroxyl group or ester moiety at C-6. Because a large number of hasubanan alkaloids follow this cleavage pattern, the metaphanine-type cleavage may be one of the primary pattern for all hasubanan alkaloids (76). 

The methyl enol ether 37 is oxidized to the a,/3-unsaturated aldehyde 39 via hemiacetal 38. Unsaturated aldehyde 39, elongated one carbon from the aldehyde 36, is prepared by the Wittig reaction of 36 to give 37, and application of this reaction[ 88]. 

Reactions of Vinyl Ethers. Vinyl ethers undergo the typical reactions of activated carbon—carbon double bonds. A key reaction of VEs is acid-catalyzed hydrolysis to the corresponding alcohol and acetaldehyde, ie, addition of water followed by decomposition of the hemiacetal. Eor example, for MVE, the reaction is... 

Conflicting findings have been reported with thiols and in one case a hemiacetal was dehydrated to a dihydrofuran. A by-product found in varying amounts in the oxidation of secondary, cyclic alcohols is the corresponding thiomethoxymethyl ether. 

The hindered 11 )5-hydroxyl group fails to react with dihydropyran. However, mixed acetals [e.g., methoxymethyl ether (97)] and hemiacetals e.g., hydroxymethyl ether (98)] are obtained as by-products in the formation of the BMD group. ... 

In steroids of the 5 -H series, however, the situation with respect to C-19 substitution changes (Figure 12-3). Displacement is now favored from 11 and abstraction from 6j5. Accordingly, 11, 19-ethers and 6/ , 19-hemiacetals or lactones are the main products. 

Note 2. Under acidic conditions and in the presence of water, the 18,20-hemiacetal formed from the 18-iodo-18,20-ether is transformed into a dimeric anhydro product, resistant to further oxidation. Pyridine is added to prevent this transformation. 

These reactions liberate carbonyl fluonde and fluorotnmethylsilane and thus require no hydrolysis A fluorinated erythromycin derivative is obtained from fluorination of 3 O raycarosyl-8 9-anhydroerythronolideB 6,9 hemiacetal, an enol ether [iS] (equation 16)... 

Animal cells can modify arachidonic acid and other polyunsaturated fatty acids, in processes often involving cyclization and oxygenation, to produce so-called local hormones that (1) exert their effects at very low concentrations and (2) usually act near their sites of synthesis. These substances include the prostaglandins (PG) (Figure 25.27) as well as thromboxanes (Tx), leukotrienes, and other hydroxyeicosanoic acids. Thromboxanes, discovered in blood platelets (thrombocytes), are cyclic ethers (TxBg is actually a hemiacetal see Figure 25.27) with a hydroxyl group at C-15. 

Aldehydes and ketones undergo acid-catalyzed reaction with alcohols to yield heniiacetals, compounds that have one alcohol-like oxygen and one ether-like oxygen bonded to the same carbon. Further reaction of a hemiacetal with alcohol then yields an iicetal, a compound that has two ether-like oxygens bonded to the same carbon. 

Nucleophilic addition of an alcohol to the carbonyl group initially yields a hydroxy ether called a hemiacetal, analogous to the gem diol formed by addition of water. HcmiacetaJs are formed reversibly, with the equilibrium normally favoring the carbonyl compound. In the presence of acid, however, a further reaction occurs. Protonation of the -OH group, followed by an El-like loss of water, leads to an oxonium ion, R2C=OR+, which undergoes a second nucleophilic addition of alcohol to yield the acetal. The mechanism is shown in Figure 19.12. 

If the carbonyl and the hydroxyl group are in the same molecule, an intramolecular nucleophilic addition can take place, leading to the formation of a cyclic hemiacetal. Five- and six-membered cyclic hemiacetals are relatively strain-free and particularly stable, and many carbohydrates therefore exist in an equilibrium between open-chain and cyclic forms. Glucose, for instance, exists in aqueous solution primarily in the six-membered, pyranose form resulting from intramolecular nucleophilic addition of the -OH group at C5 to the Cl carbonyl group (Figure 25.4). The name pyranose is derived from pyran, the name of the unsaturated six-membered cyclic ether. 

The lithium etiolate of acetaldehyde DMH has recently been utilized in the opening reaction of the ot-epoxide obtained by DM DO oxidation ofenol ether 142, to provide hemiacetal 143 after mild oxidative acid hydrolysis. The protected carbonyl functionality was subsequently used for the introduction of the trans enyne chain through a Wittig olefmation reaction to provide alcohol 144, which was then transformed into (+)-laurenyne (Scheme 8.37) [71]. 

A retroaldol fragmentation subsequent to the addition of p-TsOI I and a small amount of water to epoxide 206, obtained by oxidation of enol ether 205 with DMDO, resulted in the direct formation of dialdehyde hydrate 208, possessing the spirostructure necessary for the construction of the fused-rings core of ( )-ginkoli-de B. Apparently, hydrolysis of the epoxide produces the hemiacetal 207, which undergoes retroaldol fragmentation of the cydobutane to afford the dialdehyde, which forms the stable hydrate 208 (Scheme 8.52) [94]. 

Aldehydes and ketones can be converted to ethers by treatment with an alcohol and triethylsilane in the presence of a strong acid or by hydrogenation in alcoholic acid in the presence of platinum oxide. The process can formally be regarded as addition of ROH to give a hemiacetal RR C(OH)OR", followed by reduction of the OH. In this respect, it is similar to 16-14. In a similar reaction, ketones can be converted to carboxylic esters (reductive acylation of ketones) by treatment with an acyl chloride and triphenyltin hydride. " ... 

A more general route to 4-acetoxy-l,3-dioxanes utilizes the reductive acylation of l,3-dioxane-4-ones [46] (Scheme 21). l,3-Dioxane-4-ones 126 are prepared from the corresponding -hydroxy carboxylic acids. Low temperature reduction with DIBALH generates a diisobutylaluminum hemiacetal (127) which undergoes acylation in situ with AC2O in the presence of pyridine and DMAP. This method allows for the preparation of a wide range of 4-acetoxy-l,3-dioxanes, without the problem of a-epimerization. This method also represents a general approach to acylic a-acetoxy ethers, which are themselves useful synthetic intermediates [47,48]. 

The protection of the hemiacetal hydroxyl in Step B-2 was followed by a purification of the dominant stereoisomer. In Step C-l, the addition of the C(6) methyl group gave predominantly the undesired a-stereoisomer. The enolate was trapped as the trimethylsilyl ether and oxidized to the enone by Pd(OAc)2. The enone from sequence C was then subjected to a Wittig reaction. As in several of the other syntheses, the hydrogenation in Step D-2 was used to establish the configuration at C(4) and C(6). 

The pyranocoumarin 105 can be prepared via a three-component Diels-Alder reaction between 4-hydroxycoumarin, ethyl vinyl ether and an a-dicarbonyl compound. Similarly to the above, upon treatment of 105 with sulfuric acid in THF, hydrolysis and rearrangement occur to give the furofurochromenone 106. The hemiacetal functionality in 106 may then be oxidized with pyridinium chlorochromate (PCC) to give the lactone 107 <2001EJ03711> (Scheme 28). 

When alcohols are added to the reaction mixture, unsymmetrical ether products may be obtained. Starting with a mixture of aldehydes can also give rise to the formation of unsymmetrical ethers. These ether products are formed under conditions different from those used in the formation of ethers directly from alcohols. Thus, it is postulated that the reaction sequence that leads from the carbonyl substrate to the ether involves the intermediate formation of hemiacetals, acetals, or their protonated forms and alkoxycarbenium ions, which are intercepted and reduced to the final ether products by the organosilicon hydrides present in the reaction mix. The probable mechanistic scheme that is followed when Brpnsted acids are present is outlined in Scheme 2.311-327 328... 

Diphenylmethylsilyl-protected hemiacetals are reduced upon treatment with Ph2SiH2/Mn(CO)3Ac.295 Et SiH/TiCB reduces tert-butyldimethylsilyl ketals.306 The combination of TBSH/Sn(OTf)2 and a silyl ether converts ethylene glycol acetals and ketals into ethers (Eq. 309).501... 

A solution of the ester (56) and the tetrahydropyranyl ether (57) was irradiated to form the intermediate compound (58), which would rearrange through a retro-aldol reaction and a hemiacetal formation route to the less strained six-membered heterocycle (59). The hemiacetal (59) could be converted to loganin (55) in several steps Z3>. 

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