Synthesis and Comparison of the Reactivity of Allyl Fluorides and ...

15
Chapter One
dropped dramatically to 1 % ee when THF was used. Conversely, the enantioselectivity was
found to improve substantially (93 % ee) when the reaction was conducted in the presence
of 4 Å molecular sieves, and the temperature increased to 20 °C. Substrate (25b) gave
moderate enantioselectivities and yields for both Ni(II) and Cu(II)-catalysed reactions. The
best result achieved for Cu(II) was 84 % ee, obtained at 20 °C with TBMe, 79 % ee was
afforded for Ni(II) at 20 °C in DCM.
Scheme 1.13 Fluorination of (25a) and (25b), with (S, S)-Bis(oxazoline)-Ph (26)
Shibata has also utilised the Dbfox-Ph ligand coordinated to a Ni(II) centre to fluorinate
carbonyl compounds capable of two-point binding. [35] Previous work by the group had
found the Dbfox-Ph ligand to be highly effective in asymmetric Diels-Alder and Michael
addition reactions. [36] Reactions were conducted by treating a solution of the �-ketoester in
DCM with 1.2 equivalents of NFSI in the presence of a catalytic amount of dbfox-
Ph/Ni(ClO4).6H2O at room temperature, to afford the �-fluoro compound in good yield (76
%) and high enantioselectivity (99 %). A variety of �-ketoesters were examined, all
affording the fluorinated product in good yields and excellent enantioselectivities. The
dbfox-Ph/Ni II catalyst exhibited excellent enantioselectivity in comparison to previously
reported procedures; this is attributable to the control of the enantioface of enolates by the
dbfox-Ph/Ni II complex. However, the fluorination reaction only occurred with high
enantioselectivity for the substrates containing sterically bulky substituents located on the
ester side. For the �-keto esters with methyl or cyclohexyl ester groups, slightly lower
enantioselectivities were obtained (R= Me, 65 % ee; R= c-C6H11, 91 % ee). It was also
found that the catalyst loading could be lowered to 2 mol % without loss of
enantioselectivity. To further investigate the potential efficacy of the dbfox-Ph/Ni II
fluorination system, pharmaceutically important fluorooxindoles were also tested. Maxipost
(used to treat ischemic stroke) was obtained in a good 71 % yield and excellent 93 % ee.
This was the first example of a catalytic enantioselective preparation of Maxipost.