Unsaturated acids formation

P-Hydroxy acids lose water, especially in the presence of an acid catalyst, to give a,P-unsaturated acids, and frequendy P,y-unsaturated acids. P-Hydroxy acids do not form lactones readily because of the difficulty of four-membered ring formation. The simplest P-lactone, P-propiolactone, can be made from ketene and formaldehyde in the presence of methyl borate but not from P-hydroxypropionic acid. P-Propiolactone [57-57-8] is a usehil intermediate for organic synthesis but caution should be exercised when handling this lactone because it is a known carcinogen. 

During the preparation of the dihalo-(usually dibromo) 20-ketopregnanes, other reactive sites must be protected (e.g., addition of bromine to the A -double bond, ketal formation with a 3-ketone). An elegant method which avoids such problems has been devised by the Upjohn group in their studies on the conversion of 11-ketoprogesterone to hydrocortisone. The former is reacted with ethyl oxalate at C-2 and C-21, then addition of three moles of bromine gives a 2,21,21-tribromide. Alkaline rearrangement produces the side chain unsaturated acid, and the bromine at C-2 is subsequently removed with zinc. 

The formation of a A -3-keto-19-norsteroid from the A -3-keto-19-acid in hot pyridine solution was first reported by Hagiwara." The same product is also obtained from the j ,y-unsaturated acid under identical con-... 

In the case of y,6-unsaturated acids, five-membered rings (y-lactones) are predominantly formed (as shown above note that Markovnikov s rale is followed), but six-membered and even four-membered lactones have also been made by this procedure. There is a gem- dimethyl effect that favors formation of 7-11 membered ring lactones by this procedure. ... 

Jackman, Hamilton, and Lawlor have studied the stereochemistry of the addition of [Co(CN)5D] to a,/3-unsaturated acids and identified the product of the addition of fumarate as the threo isomer, i.e., adduct formation has occurred by a stereospecific cis addition of Co—D across the double bond 94). 

Many enzymes have absolute specificity for a substrate and will not attack the molecules with common structural features. The enzyme aspartase, found in many plants and bacteria, is such an enzyme [57], It catalyzes the formation of L-aspartate by reversible addition of ammonia to the double bond of fumaric acid. Aspartase, however, does not take part in the addition of ammonia to any other unsaturated acid requiring specific optical and geometrical characteristics. At the other end of the spectrum are enzymes which do not have specificity for a given substrate and act on many molecules with similar structural characteristics. A good example is the enzyme chymotrypsin, which catalyzes hydrolysis of many different peptides or polypeptides as well as amides and esters. 

FIGURE 25.3 The formation of linear hydroperoxides and cyclic prostanoids during peroxidation of unsaturated acids with bisallylic positions. 

As in the case of linear peroxidation products, the initiation step of the formation of isoprostanes is the abstraction of a hydrogen atom from unsaturated acids by a radical of initiator. Initiation is followed by the addition of oxygen to allylic radicals and the cyclization of peroxyl radicals into bicyclic endoperoxide radicals, which form hydroperoxides reacting with hydrogen donors. 

As mentioned earlier, oxidation of LDL is initiated by free radical attack at the diallylic positions of unsaturated fatty acids. For example, copper- or endothelial cell-initiated LDL oxidation resulted in a large formation of monohydroxy derivatives of linoleic and arachi-donic acids at the early stage of the reaction [175], During the reaction, the amount of these products is diminished, and monohydroxy derivatives of oleic acid appeared. Thus, monohydroxy derivatives of unsaturated acids are the major products of the oxidation of human LDL. Breuer et al. [176] measured cholesterol oxidation products (oxysterols) formed during copper- or soybean lipoxygenase-initiated LDL oxidation. They identified chlolcst-5-cnc-3(3, 4a-diol, cholest-5-ene-3(3, 4(3-diol, and cholestane-3 3, 5a, 6a-triol, which are present in human atherosclerotic plaques. 

Schnurr et al. [22] showed that rabbit 15-LOX oxidized beef heart submitochondrial particles to form phospholipid-bound hydroperoxy- and keto-polyenoic fatty acids and induced the oxidative modification of membrane proteins. It was also found that the total oxygen uptake significantly exceeded the formation of oxygenated polyenoic acids supposedly due to the formation of hydroxyl radicals by the reaction of ubiquinone with lipid 15-LOX-derived hydroperoxides. However, it is impossible to agree with this proposal because it is known for a long time [23] that quinones cannot catalyze the formation of hydroxyl radicals by the Fenton reaction. Oxidation of intracellular unsaturated acids (for example, linoleic and arachidonic acids) by lipoxygenases can be suppressed by fatty acid binding proteins [24]. 

The mechanism of LOX-catalyzed LDL oxidation is still not clearly understood [31]. On one hand, it has been proposed that LDL oxidation may be initiated by oxygen radicals, which are released from the active site of the enzyme. On the other hand, the formation of lipid peroxide by direct oxygenation of unsaturated acids without the participation of free... 

The low ee-values obtained with simple unsaturated acids as compared to the enamides of dehydroamino acid derivatives show that the oxygen atoms of the amide is a key to complex formation with the metal center. Knowles also proposed a quadrant model that has been adapted for many reactions [5, 22]. The mechanism of the reaction has been investigated, and it is known that the addition of the substrate to the metal is regioselective and that competing catalytic cycles can occur [5, 10, 22, 25, 27, 30-46]. 

Unsaturated acids may be split chemically at their double bonds. Permanganate-periodate oxidation has been used to produce the corresponding carboxylic acids, while an alternative technique of ozonolysis results in the formation of aldehydes and aldehyde esters. All these reaction products may be identified by GLC and the information used to determine the position of the double bond in the original fatty acid. 

S. Except for oxido-reductases, transferases, and hydrolases, most ligases (enzymes that catalyze bond formation) are entirely substrate specific. Thus, fumarate hydratase (or fumarase) reversibly and stereospecifically adds water to fumaric acid to produce (S)-( — )-malic acid only (8) (Figure 1), and another enzyme, mesaconase, adds water to mesaconic acid to form (+ )-citramalic acid (9) (Figure 2). Although no extensive studies are available, it appears that neither fumarase nor mesaconase will add water stereospecifically to any other a,(3-unsaturated acid. 

Reactions of this type provide major routes to both the monocyclic system and to 1,5-benzothiazepines. In some cases the reactions are single-stage processes but in many cases the intermediate produced by the primary formation of the S—C bond can be isolated. Thus 2-aminoethanethiol reacts with a,/3-unsaturated or j3-halogeno ketones to give (408). Similarly reaction with a,/3-unsaturated acids, esters or acid chlorides and with 3-halogenopropionyl halides gives the 5-oxo derivative (409). 2-Aminoethanethiol also reacts with activated 2-chlorobenzophenones to give 1,4-benzothiazepines. 

Fig. 3.3.1 Pathways of essential fatty acid formation from the dietary (poly)unsaturated fatty acids. The total set of elongases and desaturases has not been completely clarified. The notation (n-3) and (n-6) are alternatives for ( -3) and (co-6), respectively...

It is possible to treat ketones with allyl alcohol and an acid catalyst to give y,5-unsaturated ketones directly, presumably by initial formation of the vinylic ethers, and then Claisen rearrangement.507 In an analogous procedure, the enolates (126) of allylic esters [formed by treatment of the esters with lithium isopropylcyclohexylamide (ICA)] rearrange to y,8-unsaturated acids.508... 

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