Hemiacetals acyclic

O-protected cyclic or acyclic carbon frameworks. The choice of acetals or ethers as derivatives allows a systematic manipulation of diols and polyols. Kinetic control and a lesser affinity for protonation on sulfur compared with oxygen allows the transformation of cyclic hemiacetals into acyclic dialkyl dithioacetals. Acetal, ether, and dithioacetal derivatives are some of the pivotal intermediates needed to explore various applications of carbohydrates in synthesis. 

The formation and the hydrolysis of acyclic and cyclic acetals have been studied in rather great detail [91]. Several reviews on this topic are available [92] and some comments have been made [13] concerning the carbohydrate series. We have shown in Schemes 1,2, and 3 that a common feature of this reaction seems to be the intermediacy of an oxocarbenium ion. However, the cyclization of such an intermediate has been questioned more recently [93] in the light of the Baldwin s rules for ring closure [94]. At least for the five-membered ring, an SN2-type displacement mechanism far the protonated form (B) of die hemiacetal (A) (favorable 5-exo-tet cyclization) has been proposed rather than the unfavorable 5-endo-trig cyclization of the oxocarbenium ion (C) (Scheme 5). Except when the formation of the enol ether (D) is structurally impossible, the intermediacy of such a compound remains feasible. 

Acyclic derivative of sugars have played a significant rede in the area of synthetic carbohydrate chemistry, permitting numerous useful transformations that are not possible with the parent sugars, which exist almost exclusively in the hemiacetal form. Trapping of aldoees in die acyclic form as their dialkyl dithioacetals, by treatment with thiols in fire presence of acid, has been a synthetically important method ever since Emil Fischer s first report some 100 years ago [1], and remains an important tool in modem synthetic carbohydrate chemistry. 

Cyclizations of chloral hemiacetal derivatives of cyclic allyl alcohols were regio- and stereo-selective (Table 6, entry 1), but a mixture of regioisomers was obtained from analogous derivatives of acyclic allyl alcohols with a nonterminal double bond.93 Hemiacetal derivatives of allyl alcohols with a terminal vinyl group have been cyclized with mercury(II) acetate to give acetal derivatives of threo 1,2-diols with moderate selectivities (equation 54 and Table 15, entries 1 and 2).147 Moderate to excellent stereoselectivity has been observed in the iodocyclizations of carbonate derivatives of allyl alcohols (entries 3-5).94a The currently available results do not provide a rationale for the variation in observed stereoselectivity. 

The hemiacetal exists as an equilibrium mixture of cyclic compound 20 and its open counterpart (21), but an aldehyde addition reaction can occur only with the acyclic form A Wittig reaction of the stabilized ylide leads to an a. (3-unsaluraied ester that has the configuration with respect to the double bond. This reaction occurs under neutral conditions, so 1,4-addition of the alcohol to the a.p-unsaturated ester is avoided.6 A subsequent DIBAH reduction leads to ally lie alcohol 6 in a reaction that ordinarily shows complete 1,2-selectivit. ... 

Equilibrium constants for hydration and hemiacetal fonnation have been calculated for representative highly fluorinated ketones.5 Both reactions were substantially more favourable in cyclic than acyclic systems. 

Part of the reason for the stability of cyclic hemiacetals concerns entropy. Formation of an acyclic acetal involves a decrease in entropy (AS° negative) because two molecules are consumed for every one produced. This is not the case for formation of a cyclic hemiacetal. Since AG°= AH° -7AS°, a reaction with a negative AS° tends to have a more positive AG° in other words, it is less favourable. 

Acyclic hemiacetals form relatively slowly from an aldehyde or ketone plus an alcohol, but their rate of formation is greatly increased either by acid or by base. As you would expect, after Chapters 12 and 13, acid catalysts work by increasing the electrophilicity of the carbonyl group. 

Reminder, Cyclic hemlacetals are more stable than acyclic ones. Note how the product stays as a lactol—an acyclic hemiacetal would revert to alcohol plus aldehyde. 

The usual acid-sensitivity of acyclic acetals was similarly of no avail in the related system studied by Myers and co-workers [Scheme 2.53].111 In this case, treatment of the dimethyl acetal 55.1 with trichloroacetic acid generated an oxonium ion intermediate, that was rapidly and efficiently intercepted with hydrogen peroxide - a reagent which is much more nucleophilic than water. The resultant a-methoxyhydroperoxide 53 was then reductively cleaved under neutral conditions to produce a hemiacetal, which lost methanol to give the desired aldehyde 53.3. 

Acetals and hemiacetals imbedded in 5- and 6-membered rings are remarkably stable and their deliberate conversion to the acyclic carbonyl derivatives can be a problem. The high thermodynamic and acid stability of the corresponding 5,5-acetals can be used to liberate a carbonyl by using a 2-stage transprotection protocol. During a synthesis of the macrolide antibiotic Erythronolide B, Martin... 

Although acyclic hemiacetals are generally unstable and therefore not present in appreciable amounts at equilibrium, cyclic hemiacetals containing five- and six-membered rings are stable compounds that are readily isolated. 

Mechanism 21.12 for this reaction is identical to Mechanism 21.10, which illustrates the conversion of an acyclic hemiacetal to an acetal. 

---