11,15-Hemiacetal

The condensation of aldehydes or ketones with secondary amines leads to "encunines via N-hemiacetals and immonium hydroxides, when the water is removed. In these conjugated systems electron density and nudeophilicity are largely transferred from the nitrogen to the a-carbon atom, and thus enamines are useful electroneutral d -reagents (G.A. Cook, 1969 S.F. Dyke, 1973). A bulky heterocyclic substituent supports regio- and stereoselective reactions. 

The synthesis of 11-oxaprostaglandlns from o-glucose uses the typical reactions of gl cofuranose diacetonide outlined on p. 267. Reduction of the hemiacetal group is achieved a thioacetal. The carbon chains are introduced by Wittig reactions on the aldehyde grou] which are liberated by periodate oxidation and laaone reduction (S. Hanessian, 1979 G Lourens, 1975). 

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]. 

The 4-hydroxy-1-alkene (homoallylic alcohol) 81 is oxidized to the hetni-acetal 82 of the aldehyde by the participation of the OH group when there is a substituent at C3. In the absence of the substituent, a ketone is obtained. The hemiacetal is converted into butyrolactone 83[117], When Pd nitro complex is used as a catalyst in /-BuOH under oxygen, acetals are obtained from homoallylic alcohols even in the absence of a substituent at C-3[l 18], /-Allylamine is oxidized to the acetal 84 of the aldehyde selectively by participation of the amino group[l 19],... 

Many of the most interesting and useful reactions of aldehydes and ketones involve trans formation of the initial product of nucleophilic addition to some other substance under the reaction conditions An example is the reaction of aldehydes with alcohols under con ditions of acid catalysis The expected product of nucleophilic addition of the alcohol to the carbonyl group is called a hemiacetal The product actually isolated however cor responds to reaction of one mole of the aldehyde with two moles of alcohol to give gem mal diethers known as acetals... 

The mechanism for formation of benzaldehyde diethyl acetal which proceeds m two stages is presented m Figure 17 9 The first stage (steps 1-3) involves formation of a hemiacetal m the second stage (steps 4-7) the hemiacetal is converted to the acetal Nucleophilic addition to the carbonyl group characterizes the first stage carbocation chemistry the second The key carbocation intermediate is stabilized by electron release from oxygen... 

Steps 1-3 Acid catalyzed nucleophilic addition of 1 mole of ethanol to the carbonyl group The details of these steps are analogous to the three steps of acid catalyzed hydration in Figure 17 7 The product of these three steps is a hemiacetal... 

Steps 4-5 Conversion of hemiacetal to carbocation These steps are analogous to the formation of carbocations m acid catalyzed reactions of alcohols... 

Step 1 The peroxy acid adds to the carbonyl group of the ketone This step is a nucleophilic addition analogous to gem diol and hemiacetal formation... 

Compounds that contain both carbonyl and alcohol functional groups are often more stable as cyclic hemiacetals or cyclic acetals than as open chain compounds Examples of several of these are shown Deduce the structure of the open chain form of each... 

One of the mdustnal processes for the preparation of phenol discussed in Section 24 6 includes an acid catalyzed rearrangement of cumene hydroperoxide as a key step This reaction proceeds by way of an intermediate hemiacetal... 

You learned in Section 17 8 of the relationship among hemiacetals ketones and alcohols the for mation of phenol and acetone is simply an example of hemiacetal hydrolysis The formation of the hemiacetal intermediate is a key step in the synthetic procedure it is the step in which the aryl—oxygen bond is generated Can you suggest a reasonable mechanism for this step" ... 

Aldoses incorporate two functional groups C=0 and OH which are capable of react mg with each other We saw m Section 17 8 that nucleophilic addition of an alcohol function to a carbonyl group gives a hemiacetal When the hydroxyl and carbonyl groups are part of the same molecule a cyclic hemiacetal results as illustrated m Figure 25 3 Cyclic hemiacetal formation is most common when the ring that results is five or SIX membered Five membered cyclic hemiacetals of carbohydrates are called furanose forms SIX membered ones are called pyranose forms The nng carbon that is derived... 

FIGURE 25 3 Cyclic hemiacetal formation in 4 hydroxybutanal and 5 hydroxypentanal... 

Aldoses exist almost exclusively as their cyclic hemiacetals very little of the open chain form is present at equilibrium To understand their structures and chemical reac tions we need to be able to translate Fischer projections of carbohydrates into their cyclic hemiacetal forms Consider first cyclic hemiacetal formation m d erythrose To visualize furanose nng formation more clearly redraw the Fischer projection m a form more suited to cyclization being careful to maintain the stereochemistry at each chirality center... 

Hemiacetal formation between the carbonyl group and the C 4 hydroxyl yields the five membered furanose ring form The anomenc carbon is a new chirality center its hydroxyl group can be either cis or trans to the other hydroxyl groups of the molecule... 

Structural drawings of carbohydrates of this type are called Haworth formulas, after the British chemist Sir Walter Norman Haworth (St Andrew s University and the University of Birmingham) Early m his career Haworth contributed to the discovery that carbohydrates exist as cyclic hemiacetals rather than m open chain forms Later he col laborated on an efficient synthesis of vitamin C from carbohydrate precursors This was the first chemical synthesis of a vitamin and provided an inexpensive route to its prepa ration on a commercial scale Haworth was a corecipient of the Nobel Prize for chem istry m 1937... 

Generating Haworth formulas to show stereochemistry m furanose forms of higher aldoses is slightly more complicated and requires an additional operation Furanose forms of D ribose are frequently encountered building blocks m biologically important organic molecules They result from hemiacetal formation between the aldehyde group and the C 4 hydroxyl... 

During the discussion of hemiacetal formation in d ribose in the preceding section you may have noticed that aldopentoses have the potential of forming a six membered cyclic hemiacetal via addition of the C 5 hydroxyl to the carbonyl group This mode of ring closure leads to a and p pyranose forms... 

Because six membered rings are normally less strained than five membered ones pyranose forms are usually present m greater amounts than furanose forms at equilib rium and the concentration of the open chain form is quite small The distribution of carbohydrates among their various hemiacetal forms has been examined by using H and NMR spectroscopy In aqueous solution for example d ribose is found to contain the various a and p furanose and pyranose forms m the amounts shown m Figure 25 5 The concentration of the open chain form at equilibrium is too small to measure directly Nevertheless it occupies a central position m that mterconversions of a and p anomers and furanose and pyranose forms take place by way of the open chain form as an inter mediate As will be seen later certain chemical reactions also proceed by way of the open chain form... 

The anomeric carbon of a furanose or pyranose form of a ketose bears both a hydroxyl group and a carbon substituent In the case of 2 ketoses this substituent is a CH2OH group As with aldoses the anomeric carbon of a cyclic hemiacetal is readily identifi able because it is bonded to two oxygens... 

Although carbohydrates exist almost entirely as cyclic hemiacetals m aqueous solution they are m rapid equilibrium with their open chain forms and most of the reagents that react with simple aldehydes and ketones react m an analogous way with the carbonyl functional groups of carbohydrates... 

The carbonyl group of carbohydrates can be reduced to an alcohol function Typi cal procedures include catalytic hydrogenation and sodium borohydnde reduction Lithium aluminum hydride is not suitable because it is not compatible with the solvents (water alcohols) that are required to dissolve carbohydrates The products of carbohydrate reduc tion are called alditols Because these alditols lack a carbonyl group they are of course incapable of forming cyclic hemiacetals and exist exclusively m noncyclic forms... 

Carbohydrates are marvelous molecules In most of them every carbon bears a functional group and the nature of the functional groups changes as the molecule mterconverts between open chain and cyclic hemiacetal forms Any approach to understanding carbohydrates must begin with structure... 

Most carbohydrates exist as cyclic hemiacetals Those with five membered rings are called furanose forms those with six membered rings are called pyranose forms... 

Ketoses are characterized by the ending ulose m their name Most nat urally occurring ketoses have their carbonyl group located at C 2 Like aldoses ketoses cyclize to hemiacetals and exist as furanose or pyranose forms... 

Oxidation with Benedict s reagent (Section 25 19) Sugars that con tain a free hemiacetal function are called reducing sugars They react with copper(ll) sulfate in a sodium citrate/sodium carbonate buffer (Benedict s reagent) to form a red precipitate of copper(l) oxide Used as a qualitative test for reducing sugars... 

Furanose form (Section 25 6) Five membered nng ansing via cyclic hemiacetal formation between the carbonyl group and a hydroxyl group of a carbohydrate... 

Hemiacetal (Section 17 8) Product of nucleophilic addition of one molecule of an alcohol to an aldehyde or a ketone Hemiacetals are compounds of the type... 

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