Insights into the Synthesis of Steroidal A‐Ring Olefins. Issue 1 (January 2014)

• Record Type: Journal Article
• Authors: Varela, Carla L.; Roleira, Fernanda M. F.; Costa, Saul C. P.; Pinto, Alexandra S. C. T.; Martins, Ana I. O. S.; Carvalho, Rui A.; Teixeira, Natércia A.; Correia‐da‐Silva, Georgina; Tavares‐da‐Silva, Elisiário
• Is Part Of: Helvetica chimica acta. Volume 97:Issue 1(2014:Jan.)
• Page Start: 39
• Page End: 46
• Publication Date: 2014-01
• Subjects: Chemistry -- Periodicals; Chemistry, Analytical -- periodicals; Chimie -- Périodiques; 540
• DOI: 10.1002/hlca.201300082
• Languages: English
• ISSNs: 0018-019X

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>The classical synthesis, followed by purification of the steroidal <italic>A</italic>‐ring Δ<sup>1</sup>‐olefin, 5<italic>α</italic>‐androst‐1‐en‐17‐one (<bold>5</bold>), from the Δ<sup>1</sup>‐3‐keto enone, (5<italic>α</italic>, 17<italic>β</italic>)‐3‐oxo‐5‐androst‐1‐en‐17‐yl acetate (<bold>1</bold>), through a strategy involving the reaction of Δ<sup>1</sup>‐3‐hydroxy allylic alcohol, 3<italic>β</italic>‐hydroxy‐5<italic>α</italic>‐androst‐1‐en‐17<italic>β</italic>‐yl acetate (<bold>2</bold>), with SOCl<sub>2</sub>, was revisited in order to prepare and biologically evaluate <bold>5</bold> as aromatase inhibitor for breast cancer treatment. Surprisingly, the followed strategy also afforded the isomeric Δ<sup>2</sup>‐olefin <bold>6</bold> as a by‐product, which could only be detected on the basis of NMR analysis. Optimization of the purification and detection procedures allowed us to reach 96% purity required for biological assays of compound <bold>5</bold>. The same synthetic strategy was applied, using the Δ<sup>4</sup>‐3‐keto enone, 3‐oxoandrost‐4‐en‐17<italic>β</italic>‐yl acetate (<bold>8</bold>), as starting material, to prepare the potent aromatase inhibitor Δ<sup>4</sup>‐olefin, androst‐4‐en‐17‐one (<bold>15</bold>). Unexpectedly, a different aromatase inhibitor, the Δ<sup>3, 5</sup>‐diene, androst‐3, 5‐dien‐17‐one (<bold>12</bold>), was formed. To overcome this drawback, another strategy was developed for the preparation of <bold>15</bold> from <bold>8</bold>. The data now presented show the unequal reactivity of the two steroidal <italic>A</italic>‐ring Δ<sup>1</sup>‐ and Δ<sup>4</sup>‐3‐hydroxy allylic alcohol intermediates, 3<italic>β</italic>‐hydroxy‐5<italic>α</italic>‐androst‐1‐en‐17<italic>β</italic>‐yl acetate (<bold>2</bold>) and 3<italic>β</italic>‐hydroxyandrost‐4‐en‐17<italic>β</italic>‐yl acetate (<bold>9</bold>), towards SOCl<sub>2</sub>, and provides a new strategy for the preparation of the aromatase inhibitor <bold>12</bold>. Additionally, a new pathway to prepare compound <bold>15</bold> was achieved, which avoids the formation of undesirable by‐products.</p> </abstract>