Chain extension conjugates

Scheme 3 illustrates retrosynthetic analysis of the E and F series of PGs. The widely used Corey synthesis (2) takes notice of the presence of the two olefinic bonds in the side chains of PGF2a. The actual synthesis consists of a two-fold Wittig-type chain extension of a chiral dialdehyde equivalent with four defined stereogenic centers derived from cyclopentadiene via a series of bicyclic intermediates. A similar sequential synthesis has been developed at Upjohn Co. (la). These chemical syntheses are much more economical than enzymatic methods and are used for commercial synthesis of certain PGs. An alternative pathway pioneered by Sih is the conjugate addition approach (3). Nucleophilic addition of an E-olefinic co side-chain unit to a cyclopentenone in which the a side chain is already installed leads directly to PGE-type compounds. Untch and Stork used an co chain unit with a Z-olefinic bond (4). The most direct and flexible synthesis is the convergent three-component coupling synthesis via consecutive linking of the two side chains to unsubstituted 4-hydroxy-2-cyclopentenone derivatives (5, 6). 

Four-carbon-chain extensions have been very successful with conjugated dienes as the functionalized olefins. We have used a few other compounds also, but they are of limited value, such as N-3-butenylphthalimide. The last compound is only useful with aromatic or certain vinyl halides where mixtures of allylic amines would not be formed. A typical diene example is the reaction of vinyl bromide with butadiene and piperidine which gives E-N-(2,5-hexadienyl)-piper-idine in 70% yield (7). The product of this reaction can be reacted again and used to extend the carbon chains by six atoms (see below). The reactions of conjugated dienes can be used to produce conjugated trienes also (4). 

One product of the reaction of an amino acid with ninhydrin is the extensively conjugated purple ninhydrin product. The other major product is the aldehyde derived from the side chain of the amino acid. When valine reacts, the resulting aldehyde is 2-methylpropanal. The other products are carbon dioxide and water. 

The p-aryl amides are produced from terephthalic acid and p-phenylenediamine. They are noted for high strength and thermal resistance that arise from extensive conjugation and linear geometry that enhances chain orientation. High-strength fibers with similar properties can be manufactured from aramids and melamine. 

The first example of chain extension of a xenobiotic Involved furfural which was reported in 1887 to add a 2-carbon unit thus producing 3-(2-furyl)acryllc acid which was Isolated In rabbit urine as Its glycine conjugate ( ), Subsequent workers were not able to confirm this observation (see for leading references). 

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