General Synthesis of Prostaglandins

The hydroxy acid A was resolved with (+)-ephedrine and converted to optically active and PGEj (Ref. 2). 

The (dextrorotatory) 11,15-bis-THP ether of PGp2a was also transformed into prostaglandins of the first series by selective hydrogenation of the Z-A bond (Ref. 3). 

The necessity for producing large amounts of synthetic prostaglandins and analogs provided the impetus for a number of improvements in the bicyclo[2.2.1]heptene approach. Especially important was the development of an enantioselective modification for the synthesis of chiral prostanoids without resolution (1975) and the invention of a chiral catalyst for the stereocontrolled conversion of 15-keto prostanoids to either 15(5)- or 15(7 )- alcohols. 

In the early work on the synthesis of prostaglandins, zinc borohydride was used for the reduction of the 15-ketone function and a 1 1 mixture of epimeric 15(S)- and 15(/ )-alcohols was generally obtained. Subsequent studies led to reaction conditions for highly selective reduction to the desired 15(S)-alcohol. Some of the results are summarized in the following table. The most practical method is E which utilizes borane as the stoichiometric reductant and a chiral, enzyme-like catalyst which is shown. 

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The Baeyer-Villiger reaction has found considerable application in the synthesis of prostaglandins. One common pattern involves the use of bicyclo[2.2.1]heptan-2-one derivatives, which are generally obtained by Diels-Alder reactions. For example, compound 10 is known as the Corey lactone and has played a prominent role in the synthesis of prostaglandins.237 This compound was originally prepared by a Baeyer-Villiger oxidation of 7-(methoxymethyl)bicyclo[2.2.1]hept-5-en-2-one.238... 

Suzuki, M. Morita, Y. Koyano, H. Koga, M. Noyori, R. Three-Component Coupling Synthesis of Prostaglandins. A Simplified, General Procedure, Tetrahedron 1990,46,4809. 

This general method has also been applied to the synthesis of ( )-prostaglandin F2 15, 11-de-oxyprostaglandin E,16, 10-oxa-ll-deoxyprostaglandin Ej17 and 7-hydroxy-PGI218. 

Hydrocodone bitartrate is an opioid analgesic combination that inhibits synthesis of prostaglandins, binds to opiate receptors in CNS, and peripherally blocks pain impulse generation produces antipyresis by direct action on the hypothalamic heat-regulating center causes cough suppression by direct central action in the medulla and may produce generalized CNS depression. They are indicated in the management of mild to moderate pain. 

Hydroxycyclopentenones. In connection with a synthesis of prostaglandins, Stork et al. have developed a general synthesis of 2-alkyl-4-hydroxycyclo-pentenones (4). Base-catalyzed rearrangement of epoxy ketones of type (1)... 

Corey and coworkers , in a synthesis of prostaglandins, prepared diene 34 by alkylation of the lithiodithiane 32 with 2-bromomethyl-l,3-butadiene (equation 41). A synthesis of jasmone (35), in an overall yield of 50%, has been reported by Ellison and Woessner in which the bisdithianylethane 33 was sequentially alkylated, followed by hydrolysis and cyclization (equation 42). A similar route for preparation of 4-hydroxy-2-cyclopenten-l-ones has been reported . This method appears to provide a general route to 1,4-diketones via 1,3-dithianes. 

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