posted on 2023-11-04, 15:03authored byKenji Yamashita, Yuji Tabata, Katsuya Yamakawa, Takuya Mochizuki, Kai Matsui, Manabu Hatano, Kazuaki Ishihara
Alkynyl
addition to carbonyl compounds is a valuable synthetic
method for the preparation of versatile chiral alcohols that are widely
found in pharmaceuticals and natural products. Although a variety
of enantioselective variations have been reported, alkynyl addition
to simple ketones remains an unmet challenge due to their low reactivity
and difficult enantiofacial discrimination. Here, we report a method
for the catalytic enantioselective addition of lithium acetylide to
a variety of ketones using macrocyclic lithium binaphtholates as catalysts.
These reactions generally suffer from facile aggregation of lithium
species, which leads to less active and selective catalysts. The macrocyclic
structure designed in this study prevents such aggregation, affording
a monomeric and highly active catalyst that can furnish enantioenriched
tertiary alcohols from a variety of ketones within 5–30 min.
Moreover, the confined cavity and lipophilicity of the macrocycle
confer substrate specificity on the system, demonstrating a multiselectivity
similar to that of enzymatic reactions. Thus, these findings offer
new insights into the rational design of small-molecule artificial
enzymes that exhibit high levels of reactivity and multiselectivity.