Insights into the Synthesis of Steroidal A‐Ring Olefins |
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Authors: | Carla L Varela Fernanda M F Roleira Saul C P Costa Alexandra S C T Pinto Ana I O S Martins Rui A Carvalho Natércia A Teixeira Georgina Correia‐da‐Silva Elisiário Tavares‐da‐Silva |
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Institution: | 1. CEF, Center for Pharmaceutical Studies & Pharmaceutical Chemistry Group, Faculty of Pharmacy, University of Coimbra, PT‐3000‐548 Coimbra, (phone: +351?239?488?400;2. fax: +351?239?488?503);3. Department of Life Sciences, Faculty of Science and Technology & Centre for Neuroscience and Cell Biology (CNC), University of Coimbra, PT‐3001‐401 Coimbra;4. Biochemistry Laboratory, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, 228, PT‐4050‐313 Porto;5. Institute for Molecular and Cellular Biology (IBMC), University of Porto, Rua do Campo Alegre, 823, PT‐4150‐180 Porto |
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Abstract: | The classical synthesis, followed by purification of the steroidal A‐ring Δ1‐olefin, 5α‐androst‐1‐en‐17‐one ( 5 ), from the Δ1‐3‐keto enone, (5α,17β)‐3‐oxo‐5‐androst‐1‐en‐17‐yl acetate ( 1 ), through a strategy involving the reaction of Δ1‐3‐hydroxy allylic alcohol, 3β‐hydroxy‐5α‐androst‐1‐en‐17β‐yl acetate ( 2 ), with SOCl2, was revisited in order to prepare and biologically evaluate 5 as aromatase inhibitor for breast cancer treatment. Surprisingly, the followed strategy also afforded the isomeric Δ2‐olefin 6 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 5 . The same synthetic strategy was applied, using the Δ4‐3‐keto enone, 3‐oxoandrost‐4‐en‐17β‐yl acetate ( 8 ), as starting material, to prepare the potent aromatase inhibitor Δ4‐olefin, androst‐4‐en‐17‐one ( 15 ). Unexpectedly, a different aromatase inhibitor, the Δ3,5‐diene, androst‐3,5‐dien‐17‐one ( 12 ), was formed. To overcome this drawback, another strategy was developed for the preparation of 15 from 8 . The data now presented show the unequal reactivity of the two steroidal A‐ring Δ1‐ and Δ4‐3‐hydroxy allylic alcohol intermediates, 3β‐hydroxy‐5α‐androst‐1‐en‐17β‐yl acetate ( 2 ) and 3β‐hydroxyandrost‐4‐en‐17β‐yl acetate ( 9 ), towards SOCl2, and provides a new strategy for the preparation of the aromatase inhibitor 12 . Additionally, a new pathway to prepare compound 15 was achieved, which avoids the formation of undesirable by‐products. |
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Keywords: | Alcohols allylic 5α ‐Androsten‐17‐ones Steroids |
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