The Development of Enantioselective Friedel-Crafts Reactions to Prepare Unnatural Amino Acid Derivatives Sarah E. Reisman, Department of Chemistry, California Institute of Technology Unnatural amino acids are important building blocks for the total synthesis of natural products, as well as the development of new drugs, biological probes, and chiral small molecule catalysts. The objective of this research is to develop new catalytic, asymmetric reactions to prepare unnatural amino acids. • Development of a highly convergent enantioselective synthesis of unnatural tryptophan derivatives: R2 R1
N H
+ Me
SnCl4 (1.0 equiv) (R)-3,3'-dibromo-BINOL (20 mol %)
O
H N
OMe
O (1.2 equiv)
CO2Me R2
4Å MS (200 wt %) DCM, 20 ºC 22 examples 84-96% ee
NHAc N H
R1
• Proposed mechanism: Lewis acid and Lewis acid-assisted Brønsted acid cooperativity.
O OMe
(S)
MeO Me
N H
Ph
H BnO +
NH O
O
CF3
N H Cl
O
SnCl3 NHAc
SnCl4 Ph
H NHAc
MeO O
SnCl3 NHAc N H
H O H O Cl Sn Cl Cl Cl
fast kS
N
Ph
H
O
Ph
OMe
(R)
kR slow
H NHAc N
Ph
H
• Ongoing studies: can we utilize this type reactivity to prepare a broad range of unnatural amino acids?
