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

10
Chapter One
poor to moderate enantioselectivities (7-48 %), attributable to the unprotected hydroxyl
group. Therefore, a new range of [N-F] + reagents were synthesised, where the hydroxyl
group on the alkaloid was protected using acetyl and benzoyl groups. These were used to
fluorinate a range of imido-protected (phthaloyl, tetrachlorophthaloyl, succinoyl,
dimethylmaleoyl) phenylglycine esters (methyl, ethyl, benzyl), phenylglycinonitrile, and
phenylglycine N,N-diethylamides. Work was concentrated on N-phthaloyl-�-aminophenyl
glycine ethyl ester and phenyl glycinotrile, as the phthaloyl amino protecting group induced
a higher degree of enantioselectivity than the succinoyl and dimethylmaleoyl protected
compounds.
Scheme 1.8 Enantioselective electrophilic fluorination of N-phthaloylphenylglycine
derivatives using various [N-F] + cinchona alkaloids
The enantioselectivities obtained were higher for N-phthaloylphenylglycinonitrile than those
for N-phthaloylphenyl glycine ethyl ester. It was also observed that enantioselection was
greater when quinine and quinidine fluorinating agents were used, suggesting that methoxy
substituents on quinoline participate in the stereoselection. Another important factor in
obtaining high enantioselectivities was protection of the hydroxyl group. For the ester
derivatives, acetyl protection yielded higher enantioselectivities than the benzoyl, however,
the opposite was true in the case of the nitrile derivatives. No improvement was found in
the enantioselectivity by modifying the nature of the para substituents on the benzoyl
protecting group. Fluorination of N-phthaloyl phenylglycinonitrile with O-(p-
methoxybenzoyl)-N-fluoroquinium tetrafluoroborate afforded the highest enantioselectivity,
94 % ee.
Shibata’s group also synthesised [N-F] + reagents using cinchona alkaloid derivatives such as
[25, 27]
dihydroquinine 4-chlorobenzoate (DHQB) and dihydroquinidine acetate (DHQDA).
However, they were only used in situ and synthesised by stirring Selectfluor (1.2
equivalents) and the cinchona alkaloid (1.2 equivalents) in anhydrous MeCN with 3 Å
molecular sieves at room temperature for 1 hour. Firstly the fluorination of 2-benzyl-3H-
inden-1-yloxy-trimethyl-silane was attempted with the fluorinating reagent prepared in situ