A Brønsted base-promoted diastereoselective dimerization of azlactones

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.


Preparation and characterization of product 6
Product 2c (40 mg, 0.12 mmol) was dissolved in acetic acid/dichloromethane (242.4:3.5, 0.24 mL), cooled to 0 °C, and NaBH 4 (5.5 mg, 0.14 mmol) was added. The reaction mixture was stirred for 3 h. The crude reaction mixture was diluted with CH 2 Cl 2 (5 mL) and washed with water (10 mL). The organic layer was dried over anhydrous Na 2 SO 4 , filtered off and concentrated under reduced pressure. At this point, the crude reaction mixture was dissolved in CDCl 3 and directly send to 1 H NMR in order to see the corresponding dr.
HSQC of 6

5-Mechanism and kinetic experiments by NMR monitoring:
Reactions were carried out using NMR technique on a 500 MHz spectrometer.

S37
-Demonstration of reaction order equations for the proposed mechanism: To obtain the expected reaction order based on the proposed mechanism, one may assume, to simplify notation, in the proposed mechanism in Figure 3 of the main text: 1a is termed A, 1a' is termed A -, 3 is termed B, and 3' is termed BH. In such terms, the time dependence of [A -] may be written: Considering the equilibrium for the formation of Ain the first step is quickly achieved, , the second step may be considered the rate determining step, and one may write down the approximation: Considering Aas a steady-state, so that only a small concentration of the anion will be present (due to the high value of k -1 ), then [ − ]⁄ = 0, so that:  Table S1. One may observe in Table S1 that the integrated rate law that results in the best fit for the experimental data, measured by the R2, is the one that corresponds to the 3 / 2 reaction order (in comparison to the expected relations for other reaction orders). The adjusted data for the 3 / 2 reaction order is presented in Figure 4 of the main text.

Reaction reversibility evaluation
Reversibility study was carried out by adding the purified product 2h in the optimized reaction conditions (30 mol % of NaTCA, acetonitrile as solvent, room temperature for 1h). The crude reaction mixture was diluted with CH 2 Cl 2 and washed with water. The organic layer was dried over anhydrous Na 2 SO 4 , filtered off and concentrated under reduced pressure. An aliquot was dissolved in CDCl 3 and analyzed by 1 H NMR in order to evaluate the corresponding d.r. No reaction takes place (the reaction isn't reversible) and no differences were detected in the diastereomeric ratio (only one diastereomer could be detected, the same that the original product 2h).

Reaction reversibility study.
NMR data of product 2h after the reversibility test.

(a) (b)
Obs: Some hydrogen atoms had been omitted for more clarification and the anisotropic displacement ellipsoids are drawn at the 30% of probability level.  (3) C18-C20 1.365 (