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 products1,2,3. 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 synthesized4,5,6,7,8. 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 outset10,11. 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.
This is a preview of subscription content, access via your institution
Subscribe to Nature+
Get immediate online access to Nature and 55 other Nature journal
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
All data are available in the main text or the supplementary materials.
The Python library used for SFC–MS peak deconvolution and analysis is available on Github under the GPL 3.0 license (https://github.com/corinwagen/chromatics).
Knowles, W. S., Sabacky, M. J. & Büthe, H. Catalytic asymmetric hydrogenation employing a soluble, optically active, rhodium complex. Chem. Commun. (London) 1445–1446 (1968).
Horner, L., Siegel, H. & Büthe, H. Asymmetric catalytic hydrogenation with an optically active phosphine–rhodium complex in homogeneous solution. Angew. Chem. Int. Ed. 7, 942 (1968).
Jacobsen, E. N., Pfaltz, A. & Yamamoto, H. (eds) Comprehensive Asymmetric Catalysis Vols. 1–3 (Springer, 1999).
Katsuki, T. & Sharpless, K. B. The first practical method for asymmetric epoxidation. J. Am. Chem. Soc. 102, 5974–5976 (1980).
Jacobsen, E. N., Marko, I., Mungall, W. S., Schroeder, G. & Sharpless, K. B. Asymmetric dihydroxylation via ligand-accelerated catalysis. J. Am. Chem. Soc. 110, 1968–1970 (1988).
Noyori, R. et al. Asymmetric hydrogenation of β-keto carboxylic esters. A practical, purely chemical access to β-hydroxy esters in high enantiomeric purity. J. Am. Chem. Soc. 109, 5856–5858 (1989).
Hirao, A., Itsuno, S., Nakahama, S. & Yamazaki, N. Asymmetric reduction of aromatic ketones with chiral alkoxy-amineborane complexes. J. Chem. Soc. Chem. Commun. 315–317 (1981).
Tokunaga, M., Larrow, J. F., Kakiuchi, F. & Jacobsen, E. N. Asymmetric catalysis with water: efficient kinetic resolution of terminal epoxides by means of catalytic hydrolysis. Science 277, 936–938 (1997).
Schmidt-Dannert, C. & Arnold, F. H. Directed evolution of industrial enzymes. Trends Biotechnol. 17, 135–136 (1999).
Gao, X. & Kagan, H. B. One-pot multi-substrate screening in asymmetric catalysis. Chirality 10, 120–124 (1998).
Satyanarayana, T. & Kagan, H. B. The multi-substrate screening of asymmetric catalysis. Adv. Synth. Catal. 347, 737–748 (2005).
Kim, H. et al. A multi-substrate screening approach for the identification of a broadly applicable Diels–Alder catalyst. Nat. Commun. 10, 770 (2019).
Prieto Kullmer, C. N. et al. Accelerating reaction generality and mechanistic insight through additive mapping. Science 376, 532–539 (2022).
You, L., Zha, D. & Ansyln, E. V. Recent advances in supramolecular analytical chemistry using optical sensing. Chem. Rev. 115, 7840–7892 (2015).
Herrera, B. T., Pilicer, S. L., Ansyln, E. V., Joyce, L. A. & Wolf, C. Optical analysis of reaction yield and enantiomeric excess. A new paradigm ready for prime time. J. Am. Chem. Soc. 140, 10385–10401 (2018).
Jang, S. & Kim, H. Direct chiral 19F NMR analysis of fluorine-containing analytes and its application to simultaneous chiral analysis. Org. Lett. 22, 7804–7808 (2020).
Feagin, T. A., Olsen, D. P. V., Headman, Z. C. & Heemstra, J. M. High-throughput enantiopurity analysis using enantiomeric DNA-based sensors. J. Am. Chem. Soc. 137, 4198–4206 (2015).
Guo, J., Wu, J., Siuzdak, G. & Finn, M. G. Measurement of enantiomeric excess by kinetic resolution and mass spectrometry. Angew. Chem. Int. Ed. 38, 1755–1758 (1999).
Reetz, M. T., Becker, M. H., Klein, H.-W. & Stöckigt, D. A method for high-throughput screening of enantioselective catalysts. Angew. Chem. Int. Ed. 38, 1758–1761 (1999).
Abato, P. & Seto, C. T. EMDee: an enzymatic method for determining enantiomeric excess. J. Am. Chem. Soc. 123, 9206–9207 (2001).
Zhao, Y., Woo, G., Thomas, S., Semin, D. & Sandra, P. Rapid method development for chiral separation in drug discovery using sample pooling and supercritical fluid chromatography–mass spectrometry. J. Chrom. A 1003, 157–166 (2003).
Barhate, C. L. et al. Ultrafast chiral separations for high throughput enantiopurity analysis. Chem. Commun. 53, 509–512 (2017).
Shen, J., Ikai, T. & Okamoto, Y. Synthesis and application of immobilized polysaccharide-based chiral stationary phases for enantioseparation by high-performance liquid chromatography. J. Chromatogr. A 1363, 51–61 (2014).
Korch, K. M. et al. Selected ion monitoring using low-cost mass spectrum detectors provides a rapid, general, and accurate method for enantiomeric excess determination in high-throughput experimentation. ACS Catal. 12, 6737–6745 (2022).
Payne, C. & Kass, S. R. How reliable are enantiomeric excess measurements obtained by chiral HPLC? ChemistrySelect 5, 1810–1817 (2020).
Annesley, T. Ion suppression in mass spectrometry. Clin. Chem. 49, 1041–1044 (2003).
George, R. et al. Enhancement and suppression of ionization in drug analysis using HPLC-MS/MS in support of therapeutic drug monitoring: a review of current knowledge of its minimization and assessment. Ther. Drug. Monit. 40, 1–8 (2018).
Cox, E. D. & Cook, J. M. The Pictet-Spengler condensation: a new direction for an old reaction. Chem. Rev. 95, 1797–1842 (1995).
Stöckigt, J., Antonchick, A. P., Wu, F. & Walmann, H. The Pictet–Spengler reaction in nature and in organic chemistry. Angew. Chem. Int. Ed. 50, 8538–8564 (2011).
Taylor, M. S. & Jacobsen, E. N. Highly enantioselective catalytic acyl-Pictet–Spengler reactions. J. Am. Chem. Soc. 126, 10558–10559 (2004).
Seayad, J., Seayad, A. M. & List, B. Catalytic asymmetric Pictet–Spengler reaction. J. Am. Chem. Soc. 128, 1086–1087 (2006).
Wanner, M. J., van der Haas, R. N. S., de Cuba, K. R., van Maarseveen, J. H. & Hiemstra, H. Catalytic asymmetric Pictet–Spengler reactions via sulfenyliminium ions. Angew. Chem. Int. Ed. 46, 7485–7487 (2007).
Raheem, I. T., Thiara, P. V., Peterson, E. A. & Jacobsen, E. N. Enantioselective Pictet–Spengler-type cyclizations of hydroxylactams: H-bond donor catalysis by anion binding. J. Am. Chem. Soc. 129, 13404–13405 (2007).
Sewgobind, N. V. et al. Enantioselective BINOL-phosphoric acid catalyzed Pictet−Spengler reactions of N-benzyltryptamine. J. Org. Chem. 73, 6405–6408 (2008).
Huang, D., Xu, F., Lin, X. & Wang, Y. Highly enantioselective Pictet–Spengler reaction catalyzed by SPINOL‐phosphoric acids. Chem. Eur. J. 18, 3148–3152 (2012).
Mittal, N., Sun, D. X. & Seidel, D. Conjugate-base-stabilized Brønsted acids: catalytic enantioselective Pictet–Spengler reactions with unmodified tryptamine. Org. Lett. 16, 1012–1015 (2014).
Qi, L., Hou, H., Ling, F. & Zhong, W. The cinchona alkaloid squaramide catalyzed asymmetric Pictet–Spengler reaction and related theoretical studies. Org. Biomol. Chem. 16, 566–574 (2018).
Glinsky-Olivier, N., Yang, S., Retailleau, P., Gandon, V. & Guinchard, X. Enantioselective gold-catalyzed Pictet–Spengler reaction. Org. Lett. 21, 9446–9451 (2019).
Kondo, M. et al. Practical stereoselective synthesis of C3‐spirooxindole‐ and C2‐spiropseudoindoxyl‐pyrrolidines via organocatalyzed Pictet‐Spengler reaction/oxidative rearrangement sequence. Adv. Synth. Catal. 363, 2648–2663 (2021).
Lynch-Colameta, T., Greta, S. & Snyder, S. A. Synthesis of aza-quaternary centers via Pictet–Spengler reactions of ketonitrones. Chem. Sci. 12, 6181–6187 (2021).
Muratore, M. E. et al. Enantioselective Brønsted acid-catalyzed N-acyliminium cyclization cascades. J. Am. Chem. Soc. 131, 10796–10797 (2009).
Klausen, R. S. & Jacobsen, E. N. Weak Brønsted acid-thiourea co-catalysis: enantioselective, catalytic protio-Pictet-Spengler reactions. Org. Lett. 11, 887–890 (2009).
Nakamura, S., Matsuda, Y., Takehara, T. & Suzuki, T. Enantioselective Pictet−Spengler reaction of acyclic α‐ketoesters using chiral imidazoline-phosphoric acid catalysts. Org. Lett. 24, 1072–1076 (2022).
Chan, Y.-C., Sak, M. H., Frank, S. A. & Miller, S. J. Tunable and cooperative catalysis for enantioselective Pictet-Spengler reaction with varied nitrogen-containing heterocyclic carboxaldehydes. Angew. Chem. Int. Ed. 60, 24573–24581 (2021).
McInnes, L., Healy, J. & Melville, J. UMAP: uniform manifold approximation and projection for dimension reduction. Preprint at https://arxiv.org/abs/1802.03426 (2018).
We thank J. Gair, R. Klausen, R. Liu, A. Makarov, L. Nogle and E. Regalado for helpful discussions. This work was supported by a NIH grant GM043214 (E.N.J.), Dean’s Competitive Fund, Harvard University (E.N.J.) and NSF predoctoral fellowship DGE1745303 (C.C.W.).
The authors declare no competing interests.
Peer review information
Nature thanks Andrea Gargano and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Sections 1–6, including general information, details regarding analytical method development and validation text, application to the Pictet–Spengler reaction, References, NMR spectra data and further Supplementary Data. These sections include Supplementary Figs. 1–47 and Tables 1–10.
About this article
Cite this article
Wagen, C.C., McMinn, S.E., Kwan, E.E. et al. Screening for generality in asymmetric catalysis. Nature 610, 680–686 (2022). https://doi.org/10.1038/s41586-022-05263-2
This article is cited by