A Brønsted base-promoted diastereoselective dimerization of azlactones

Abstract

A novel Brønsted base system for the diastereoselective dimerization of azlactones using trichloroacetate salts and acetonitrile has been developed. Desired products were obtained in good yields (60-93%) and with up to >19:1 dr after one hour of reaction. Additionally, the relative stereochemistry of the major dimer was assigned as being trans, by X-ray crystallographic analysis. The kinetic reaction profile was determined by using ¹H NMR reaction monitoring and revealed a second order overall kinetic profile. Furthermore, by employing this methodology, a diastereoselective total synthesis of a functionalized analogue of streptopyrrolidine was accomplished in 65% overall yield.

Keywords: azlactones; diasteoreselective synthesis; dimerization; kinetics; streptopyrrolidine analogue.

Figure 1

Structure of an azlactone dimer.

Scheme 1

Diastereoselective dimerization of azlactones. Reactions were carried out using 0.45 mmol of 1 and 0.14 mmol of salt. Diastereomer ratio measured by ¹H NMR analysis of the crude reaction mixture.

Figure 2

X-ray crystallographic structure of 2a (30% ellipsoids probability).

Scheme 2

Sterically bulky azlactone enol derivatives.

Figure 3

Plausible mechanism for the dimerization of azlactone.

Figure 4

Plot of vs time for the dimerization of azlactone 1a.

Scheme 3

Reduction of 2c.

Figure 5

X-ray crystallographic structure of 6 (30% ellipsoids probability).