Synthesis of ,-unsaturated amino acids via palladium-catalyzed allylic
alkylation of chelated glycine ester enolates
Uli Kazmaier*, Michael Bauer
Recent Res. Devel. 2005, 9, 49-69
Chelated amino acid ester enolates are suitable nucleophiles for palladium-catalyzed allylic
alkylation reactions. Their high reactivity permits the reaction to be performed at temperatures
as low as –78 °C – conditions at which -- isomerization can be suppressed. Thus, starting
from 1,3-disubstituted allylic substrates, ,-unsaturated amino acid derivatives are obtained
in a highly diastereoselective fashion, giving rise to anti-configured products. The absolute
stereochemistry of the two newly formed stereogenic centers can easily be controlled either
by the use of chiral ligands or via chirality transfer from optically active allylic substrates.
(Z)-configured amino acid derivatives are achieved by selectively attacking anti/syn allylpalladium complexes at the syn position, whereas on the other hand, the more reactive
anti-position can be utilized to approach a regioselective process. A bit different is the
situation when monosubstituted allylic substrates are employed. In that case the
stereochemical outcome of the reaction is solely controlled by the configuration of a chiral
center situated next to the allyl moiety, again providing diastereomerically enriched material
with excellent selectivities. Subjecting the C-allylation products to an N-allylation step and
subsequent ring closing metathesis in the issue provides a facile route to cyclic amino acid
derivatives like pipecolinic acid. Being complementary to the chelate enolate Claisen
rearrangement with regard to diastereoselectivity, the palladium-catalyzed allylic alkylation of
chelated glycine ester enolates thereby proves to be a versatile tool in the field of
stereoselective synthesis of unnatural amino acids.