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provided by dienone 4. No improvements were observed when unsatisfactory results were obtained. 1,6-Addition of 16 to give
changing the reaction temperature (entries 9 and 10). 5 provided 40% of the desired 7a-isomer, but it was obtained as
We have run the formation of 12 on a gram scale with no an inseparable 4 :1 mixture with alcohol 8. Hydrometallation of
loss of yield or selectivity. With 12 in hand (Scheme 2), we used 17 was not effective and 1,6-addition products were not obtained.
a mixture of CuBr2 and LiBr to aromatize the enone to 13 (77%)
In conclusion, an alternative synthetic route to fulvestrant
without any observable over-bromination products;15 aromatization involving hydrozirconation of a commercially available alkene
is required at this stage to avoid conjugate addition of thiol to the and copper-catalyzed 1,6-addition has been developed. As the
enone unit in the next step.
reaction tolerates an alkylbromide the 1,6-addition product can
In situ hydrolysis of (4,4,5,5,5)-pentafluoropentyl ethanthiolate be readily functionalized, avoiding use of 2 and streamlining the
1420 at 40 1C liberates the thiol, displacing the bromide and synthesis. The main cause of source of impurities in previous
giving 15 (80%); these conditions avoid isolation of malodorous routes was the use of 2. Diastereoselectivity of 4.6 : 1 in favour of
(4,4,4,5,5)-pentafluoropentanthiol and remove the acetate protecting the desired a-anomer is observed using 10 mol% of a chiral copper
group on the 17b alcohol moiety.
catalyst. The overall yield of the four-step sequence is 35%.
Oxidation to sulfoxides 1 (35% H2O2, AcOH, EtOAc, 40 1C)
gave no observable overoxidation, and fulvestrant 1 as a B1 : 1
mixture of isomers (observable by 13C NMR) in 95% yield.
We also examined hydrometallation-addition of alkenes
bearing a sulphide and sulfoxide (Scheme 3). In both cases
Notes and references
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Scheme 2 Synthesis of fulvestrant.
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Scheme 3 1,6-Addition of alkyl chains bearing a sulphur atom. Reaction
conditions: 4 (1.0 eq.), A (20 mol%), CuCl (20 mol%), AgOTf (22 mol%),
alkene (2.5 eq.), Cp2ZrHCl (2.0 eq.), TMSCl (5 eq.).
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