Application of Isocyanides Derived from α-Amino Acids as Substrates for the Ugi Reaction

Abstract

A systematic study on the influence of Lewis acid, solvent, and temperature on the stereochemical course of the Ugi reaction was performed to find conditions in which the isocyanides derived from enantiopure α-amino acids do not racemize. After a series of experiments, dichloromethane was used as a solvent and BF₃ · OEt₂ as a Lewis acid catalyst. This combination allowed us to obtain a product in a model reaction with 99% diastereoisomeric ratio (dr), with the structure motif of a group of cathepsin K inhibitors.

Keywords:

• Isocyanides
• racemization
• Ugi reaction

ACKNOWLEDGMENT

This work was financially supported by Polish State Committee for Scientific Research, Grant N405 007 31/0544.

Notes

^a Abbreviations used: TEA—triethylamine, NMM—4-methylmorpholine.

^b Published data^{[ 5 ]}: [α]^D ₂₀ = − 13.2 (c = 1.3, benzene), mp = 58–59 °C.

^c Benzene used as a solvent, c = 1.3.

^a Reaction time prolonged to 210 h.

^a Excess of reagent used as solvent.