Unnatural prostaglandins

Prostaglandins (PG) were discovered in human semen more than 50 years ago. Their name derives from the prostate gland, but they are produced in many tissues. In fact, the high concentrations found in semen arise in the seminal vesicles rather than the prostate. The chemical parent compound is a 20 carbon unnatural fatty acid known as prostanoic acid that contains a five-membered (cyclopentane) ring. Derivatives that contain this structure (PGs, TXs, and PGIs) are known collectively as prostanoids. 

The prostaglandins prostacyclin and thromboxane, collectively termed prostanoids, can be considered analogs of unnatural compounds with the trivial names prostanoic acid and thrombanoic acid, with the structures shown below ... 

Chemical resolution of a meso-elio/. Acylation of the symmetrical meyo-diol ciy-2-cyclopentene-l,4-diol (2) with 1 equiv. of the chiral reagent 1 in pyridine affords a mixture of the monoesters 3 and 4 in 517 yield, together with some of the diester. The mono esters were separated readily by fractional crystallization to give pure, optically active 3 and 4. These esters were converted into the (+ )-and ( —)-5 hydroxy ethers, respectively, and then into the optically active lactones ( + )- and (—)-6 by Claisen rearrangement and lactonization (6, 608-609). These lactones have been converted into both natural and unnatural prostaglandins. See scheme (I) at top of page 321. 

The isolation and purification of the prostaglandins by Bergstrom in the 1950s [6-7], and the subsequent structure determination and development of laboratory scale biosynthesis led to the extensive studies of their effects on numerous biological systems. More recently, total chemical syntheses have provided further sources of the natural prostaglandins as well as unnatural structural variants and stereoisomers. 

Following the publication in 1966 of the first route to a biologically active prostaglandin [115], many total chemical syntheses of the natural prostaglandins and their structural variants have been reported. Here syntheses of the four main groups—PGE, F, A and B—and their unnatural stereoisomers are discussed first, followed by an account of routes to dihydroprostaglandins and novel derivatives of prostanoic acid. See also note on p. 366. 

In addition to the above structural analogues, syntheses have been reported of unnatural epimers and enantiomers of the natural prostaglandins [176,177]. 

The report will be divided into two sections (a) Syntheses of natural prostaglandins and (b) Syntheses of unnatural prostanoic acids and related analogs. Since PGEs can be transformed to PGFs and PGAs, any synthesis of PGE also constitutes, in principal, a synthesis of the corresponding PGF and PGA. ... 

These workers (10,11) have also utilized O2 to achieve an important synthetic objective in the prostaglandin field, namely the efficient conversion of 15-R (unnatural) prostaglandins into the 15- (natural) Isomers by nucleophilic displacement. These data all demonstrate the Sjj2 inversion character of 02 reacting with alkyl halides and sulfonate esters. 

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