Prostaglandins Prins reaction

In an early step in an enantioselective total synthesis of certain prostaglandins <88T4989,92T10345>, application of the Prins reaction conditions to an unsaturated bicyclic lactone or ether (Equation (11)) afforded tricyclic heterocycles (31) containing cyclopentane-fused tetrahydrofuran and 1,3-dioxane units in 4-10% yield. The major products in each case were bicyclic diacetate derivatives of the starting material. 

The cyclopropyl ketone displayed in equation 47—accessible from norbornadiene and formaldehyde via the Prins reaction—can serve as a versatile starting material for the synthesis of prostaglandins , pseudoguainolides " and steroidsStereochemical aspects of HBr addition to cyclopropyl ketones have been studied . 

Prins reactions with formaldehyde have been used to prepare prostaglandin intermediates. Reaction of norbomadiene with paraformaldehyde and formic acid at -80 °C gives (6) in 67% yield (equation 3). Reaction of unsaturated lactone (7) with formaldehyde in acetic acid at 60-80 C gives prostaglandin intermediate (8) in 75-85% yield (equation 4). Addition of protonated formaldehyde occurs from the less-hindered face of the double bond followed by trans addition of acetate to the carbocation. 

The Prins reaction with formaldehyde is a well-known route to prostaglandins using bicyclic lactone 3 as a precursor. One synthesis of this lactone14 started this sequence with a Prins reaction. Treatment of norbomadiene with paraformaldehyde in the presence of formic acid produced a mixture of epimeric diformates in 67% yield which were transformed in several steps into lactone 3. A second synthesis starts with the unsaturated bicyclic lactone which undergoes attack by the oxonium ion both regio- and stereoselectively from the less hindered face of the double bond, trims Addition of the nucleophilic acetate generates the lactone 3 as the bisacetate derivative15. 

The use of bicyclo(2,2,l)-heptane derivatives in natural product synthesis has been explored extensively by Grieco and co-workers. They have devised a synthesis of ( )-estrone based on orthoquinodimethane methodology in which e ring D component is derived stereospecihcally from the bicyclo-(2,2,l)heptane species 134 (Scheme 18). The latter and related bicycloheptanes are readily available from norbomadiene by a sequence which features e Prins reaction, devised independently by groups led by Corey and Sutherland in conjunction with their studies on prostaglandin synthesis. 

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