Screening for generality in asymmetric catalysis

Abstract

Research in the field of asymmetric catalysis over the past half century has resulted in landmark advances, enabling the efficient synthesis of chiral building blocks, pharmaceuticals and natural products^1-3. A small number of asymmetric catalytic reactions have been identified that display high selectivity across a broad scope of substrates; not coincidentally, these are the reactions that have the greatest impact on how enantioenriched compounds are synthesized^4-8. We postulate that substrate generality in asymmetric catalysis is rare not simply because it is intrinsically difficult to achieve, but also because of the way chiral catalysts are identified and optimized⁹. Typical discovery campaigns rely on a single model substrate, and thus select for high performance in a narrow region of chemical space. Here we put forth a practical approach for using multiple model substrates to select simultaneously for both enantioselectivity and generality in asymmetric catalytic reactions from the outset^10,11. Multisubstrate screening is achieved by conducting high-throughput chiral analyses by supercritical fluid chromatography-mass spectrometry with pooled samples. When applied to Pictet-Spengler reactions, the multisubstrate screening approach revealed a promising and unexpected lead for the general enantioselective catalysis of this important transformation, which even displayed high enantioselectivity for substrate combinations outside of the screening set.

Fig. 1.. Approaches to the discovery and analysis of enantioselective reactions.

(A) The standard approach to discovery of new asymmetric catalytic reactions involves optimization around a single model substrate. The scope of the method is then examined in a separate exercise, often resulting in methods that are only highly effective for substrates similar to the model. (B) Optimization via multi-substrate screening across a broad cross-section of substrate space improves the chances of identifying more general catalysts and conditions. (C) Conventional ee determination of single isolated products via chromatography on CSPs and detection by UV-Vis. (D) High-throughput ee determination of multiple products via SFC-MS. As long as each product possesses a unique mass and because enantiomers have equal response factors, multiple enantioselectivity values can be measured simultaneously by direct integration of the extracted ion chromatograms (EICs).

Fig. 2:. Development of the SFC-MS method.

(A) Combining Gaussian and Voigt functions provides accurate integration of poorly separated peaks (“det’d” refers to ee determined by SFC-MS). (B) Heatmap visualization of the total ion chromatogram. (C) Analysis of 20 pooled racemic compounds by SFC-MS (RMSE=7%, n=58). (D) Pairwise experiments with racemates reveals that co-elution can result in ion suppression, leading to inaccurate ee values. When columns and pooling combinations that minimize co-elution with strong ionizers are used, typical errors are 5–10% ee.

Fig. 3.. High throughput ee-determination of enantioselective catalytic Pictet–Spengler reactions

(A) The 14-member panel of products (left) used to study the Pictet–Spengler reaction and a map (right) of potential products (grey) with previously reported products from the literature (blue) vs. our panel (red). Test products (yellow) excluded from the initial screens were evaluated after all optimization studies were completed (Fig. 4C). Map generated by UMAP dimensionality reduction of product molecular fingerprints. (B) Enantioselectivity screen using 14 previously reported organocatalysts against the 14-member panel. Reactions with weakly acidic H-bond-donor catalysts i–ix and xiii–xiv were run with benzoic acid as a co-catalyst. Empty squares represent low-yielding reactions. A metric (g) was constructed to quantify the degree of generality exhibited by each catalyst.

Fig. 4.. Further reaction optimization and validation.

(A) Solvent screening reveals the beneficial effects of 2-methyl THF (2MT) compared to toluene (PhMe) and ethyl acetate (EA) for most substrate combinations. (B) Rerunning the optimal conditions with conventional glassware with molecular sieves results in improved enantioselectivity for some substrates, and diminished enantioselectivity for others. (C) Assessment of previously untested substrate combinations leading to products 14, 20, and 36 under the high-throughput screening conditions with four selected catalysts. In each case, catalyst xii displayed the highest enantioselectivities, consistent with the results of the generality screen.