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Insights into the Synthesis of Steroidal A ‐Ring Olefins
Author(s) -
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.,
CorreiadaSilva Georgina,
TavaresdaSilva Elisiário
Publication year - 2014
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.201300082
Subject(s) - chemistry , aromatase , enone , olefin fiber , allylic rearrangement , steroid , reactivity (psychology) , alcohol , ring (chemistry) , aromatase inhibitor , stereochemistry , catalysis , organic chemistry , breast cancer , cancer , biochemistry , hormone , medicine , alternative medicine , pathology
The classical synthesis, followed by purification of the steroidal A ‐ring Δ 1 ‐olefin, 5 α ‐androst‐1‐en‐17‐one ( 5 ), from the Δ 1 ‐3‐keto enone, (5 α ,17 β )‐3‐oxo‐5‐androst‐1‐en‐17‐yl acetate ( 1 ), through a strategy involving the reaction of Δ 1 ‐3‐hydroxy allylic alcohol, 3 β ‐hydroxy‐5 α ‐androst‐1‐en‐17 β ‐yl acetate ( 2 ), with SOCl 2 , 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 Δ 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 Δ 4 ‐3‐keto enone, 3‐oxoandrost‐4‐en‐17 β ‐yl acetate ( 8 ), as starting material, to prepare the potent aromatase inhibitor Δ 4 ‐olefin, androst‐4‐en‐17‐one ( 15 ). Unexpectedly, a different aromatase inhibitor, the Δ 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 Δ 1 ‐ and Δ 4 ‐3‐hydroxy allylic alcohol intermediates, 3 β ‐hydroxy‐5 α ‐androst‐1‐en‐17 β ‐yl acetate ( 2 ) and 3 β ‐hydroxyandrost‐4‐en‐17 β ‐yl acetate ( 9 ), towards SOCl 2 , 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.