Enantiodivergence by minimal modification of an acyclic chiral secondary aminocatalyst

The development of enantiodivergent catalysis for the preparation of both enantiomers of a chiral compound is of importance in pharmaceutical and bioorganic chemistry. With the design of a class of reactive and stereoselective organocatalysts, acyclic chiral secondary amines, a method for achieving the enantiodivergence is developed simply by changing the secondary N-i-Bu- to N-Me-group within the catalyst architecture while maintaining the same absolute configuration of the catalysts, which modulates the catalyst conformation. This catalyst-controlled enantiodivergent method not only enables challenging asymmetric transformations to occur in an enantiodivergent manner but also features a high level of stereocontrol and broad scope that is demonstrated in eight different reactions (90 examples), all delivering both enantiomers of a range of structurally diverse products including hitherto less accessible, yet important, compounds in good yields with high stereoselectivities.


yl)carbamate
Following the General Procedure B2, (R,S)-3h was obtained as white solid (14

yl)carbamate
Following the General Procedure C1, (S,R)-5a was obtained as white solid (18 h

yl)carbamate
Following the General Procedure C2, (R,S)-5a was obtained as white solid (18 h

yl)carbamate
Following the General Procedure D2, (R,S)-7c was obtained as white solid (18 h

yl)carbamate
Following the General Procedure D1, (S,R)-7f was obtained as white solid (6 h

yl)carbamate
Following the General Procedure D2, (R,S)-7f was obtained as white solid (14 h
The absolute configuration of 5d obtained from the Gerneral Precedure C1 was confirmed to be S,R by X-ray analysis ( Supplementary Fig. 3), and accordingly the reaction enantioselectivity and its enantiomer obtained from the Gerneral Precedure C2 in other cases was assigned by analogy.  (8) According to the reported similar products, 2 the abosulte configruation of oxindolederived Mannich products 7 obtained from Generenal Procedure D1 were assigned to be S,R. And the abosulte configruation of Mannich products 7 obtained from Generenal Procedure D2 were R,S by analoy.
The absolute configuration of 9 obtained from the Gerneral Precedure E1 was confirmed to be S,R by X-ray analysis ( Supplementary Fig. 4), and accordingly its enantiomer obtained from the Gerneral Precedure E2 in other cases was assigned by analogy.  (11) Supplementary Figure 5. Crystal Structure of (R,R)-11a.

Supplementary
The absolute configuration of 11a obtained from the Gerneral Precedure F1 was confirmed to be R,R by X-ray analysis ( Supplementary Fig. 5), and accordingly the reaction enantioselectivity and its enantiomer obtained from the Gerneral Precedure F2 in other cases was assigned by analogy.  For the asymmetric Mannich reaction between the β,γ-alkynyl-α-imino ester 1a and propionaldehyde 2a catalyzed by Ia ( Supplementary Fig. 7), the solvent effects were considered by with an SMD solvation model in the MeCN solvent. For the reversal enantioselective Mannich reaction catalyzed by Id ( Supplementary Fig. 8  As shown in Supplementary Fig. 6, according to the density functional theory (DFT) calculations, the E-s-trans enamine species generated from N-R 2 amino-catalysts (R 2 = iBu, nPr, Et) and propionaldehyde 2a were preferred to s-syn C-N skeleton of enamine conformation int-I ( Supplementary Fig. 6a, 6b, 6c and 6e ), while s-anti C-N skeleton of enamine conformation int-II were favorable for enamine species generated from N-Me amino-catalysts (Supplementary Fig. 6d and 6f). Typically, the related free energy of s-syn C-N skeleton of enamine conformation Ia-int-I generated from N-i-Bu amines Ia and aldehyde 2a was 1.6 kcal/mol lower than that of s-anti Ia-int-II, in which the repulsion is severe (Supplementary Fig. 6a). Whereas the enamine species s-anti Id-int-II generated from N-Me amines Id and aldehyde 2a has a less steric crowding than s-syn If-int-I resulting in an exotherm of 1.9 kcal/mol ( Supplementary Fig. 6f).

TS-I-(Ia-S,R) TS-II-(Ia-R,S) TS-V (Ia-R,R) TS-VI (Ia-S,S)
Newman projections about the C−N bond reveals that the repulsion between adjacent groups leads to the different thermal stability of enamine species. The free energy discrepancy well correlates with substituents' volume N atom adjacent to C=C bond.
Notably, the corresponding differences in the free energies are in reasonable agreement To further shed light on the origin of the observed stereoselective reversal, the antiselective enantiodivergent Mannich reactions exemplified by ketimine 1a and aldehyde 2a was investigated computationally by density functional theory (DFT) calculations.
As Supplementary Fig. 7 and 8 shown, four diastereomeric transition states for the C-C bond-formation step have been proposed to be a 9-membered cycle. 12 For the Mannich reaction catalyzed by N-i-Bu amines 1a ( Supplementary Fig. 7), TS-I, TS-II lead to the major and the minor enantiomers for major product diastereomers, dihedral-angle value of 3.2 o . The relative free energy of TS-I is 2.2 kcal/mol than that of TS-II, which is in agreement with the computed energy difference of enamines species between s-syn Ia-int-I and s-anti Ia-int-II. Thus, we presume that the strain resulted by conformation of C-N skeleton is the main factor for the enantiocontrol in   results show that the nucleophilic addition is the rate-and enantioselective-determining step among the reaction pathway, and the overall activation free energy is determined to be 22.7 kcal/mol.