We have developed new C
1-symmetric,
chiral bis-phosphoric acids with an electron-withdrawing group as
one of the two substituents. This C
1-symmetric,
chiral bis-phosphoric acid with a pentafluorophenyl group performs
exceptionally well in the asymmetric Diels–Alder reaction of
acrolein, methacrolein, and α-haloacroleins with substituted
amidodienes. Control over the atropisomeric catalyst structure, enhancement
of the catalytic activity, and differentiation of the asymmetric reaction
space is possible by the remote control of the pentafluorophenyl group.
Furthermore, we have conducted theoretical studies to clarify the
roles of both intra- and intermolecular hydrogen bonds in the C
1-symmetric chiral environment of chiral bis-phosphoric
acid catalysts. The developed strategy, C
1-symmetric catalyst design through hydrogen bonding, is potentially
applicable to the development of other chiral Brønsted acid catalysts.
A chiral Brønsted acid containing two different acidic sites, chiral carboxylic acid-monophosphoric acid 1a, was designed to be a new and effective concept in catalytic asymmetric hetero-Diels-Alder reactions of azopyridinecarboxylate with amidodienes. The multipoint hydrogen-bonding interactions among the carboxylic acid, monophosphoric acid, azopyridinecarboxylate, and amidodiene achieved high catalytic and chiral efficiency, producing substituted 1,2,3,6-tetrahydropyridazines with excellent stereocontrol in a single step. This constitutes the first example of regio-, diastereo-, and enantioselective azo-hetero-Diels-Alder reactions by chiral Brønsted acid catalysis.
Two 4-ethoxycarbonyl thiazolyl groups were introduced into 2- and 5-positions of 3-hydroxypyridine in 8 steps using 5-cyano-3-hydroxypyridine (2) as the starting material. The pyridine derivative obtained in the last step was converted to a fragment A derivative (21) by stepwise introduction of the 2-substituted 4-thiazolyl group into the 6-position. The total yield for the formation of 21 via 14 steps was 7.6%.
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