Insights into the Synthesis of Steroidal A-Ring Olefins

• Type: Article in International Scientific Journal
• Date: 2014

Authors

Carla L Varela (Author) Other; Fernanda M F Roleira (Author) Other; Saul C P Costa (Author) Other; Alexandra S C T Pinto (Author) Other; Ana I O S Martins (Author) Other; Rui A Carvalho (Author) Other; Natercia A Teixeira (Author) FFUP; Georgina Correia da Silva (Author) FFUP; Elisiario Tavares da Silva (Author) Other

Journal

Title: Helvetica Chimica Acta

Vol. 97

Pages: 39-46

ISSN: 0018-019X

Publisher: Wiley-Blackwell

Indexing

ISI Web of Knowledge - 2 Citations

Scopus - 3 Citations

Scientific classification

FOS: Natural sciences > Chemical sciences

Other information

Authenticus ID: P-009-3JE

DOI: 10.1002/hlca.201300082

Abstract (EN): The classical synthesis, followed by purification of the steroidal A-ring (1)-olefin, 5-androst-1-en-17-one (5), from the (1)-3-keto enone, (5,17)-3-oxo-5-androst-1-en-17-yl acetate (1), through a strategy involving the reaction of (1)-3-hydroxy allylic alcohol, 3-hydroxy-5-androst-1-en-17-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 (2)-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 (4)-3-keto enone, 3-oxoandrost-4-en-17-yl acetate (8), as starting material, to prepare the potent aromatase inhibitor (4)-olefin, androst-4-en-17-one (15). Unexpectedly, a different aromatase inhibitor, the (3,5)-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 (1)- and (4)-3-hydroxy allylic alcohol intermediates, 3-hydroxy-5-androst-1-en-17-yl acetate (2) and 3-hydroxyandrost-4-en-17-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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 8