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Predicting Glycosylation Stereoselectivity Using Machine Learning† Cite This: Chem Chemical Science View Article Online EDGE ARTICLE View Journal | View Issue Predicting glycosylation stereoselectivity using machine learning† Cite this: Chem. Sci.,2021,12,2931 ab a ab All publication charges for this article Sooyeon Moon, ‡ Sourav Chatterjee, ‡ Peter H. Seeberger have been paid for by the Royal Society and Kerry Gilmore §*a of Chemistry Predicting the stereochemical outcome of chemical reactions is challenging in mechanistically ambiguous transformations. The stereoselectivity of glycosylation reactions is influenced by at least eleven factors across four chemical participants and temperature. A random forest algorithm was trained using a highly reproducible, concise dataset to accurately predict the stereoselective outcome of glycosylations. The steric and electronic contributions of all chemical reagents and solvents were quantified by quantum mechanical calculations. The trained model accurately predicts stereoselectivities for unseen nucleophiles, electrophiles, acid catalyst, and solvents across a wide temperature range (overall root mean square error 6.8%). All predictions were validated experimentally on a standardized microreactor platform. The model helped to identify novel ways to control glycosylation stereoselectivity and Creative Commons Attribution 3.0 Unported Licence. Received 11th November 2020 accurately predicts previously unknown means of stereocontrol. By quantifying the degree of influence Accepted 24th December 2020 of each variable, we begin to gain a better general understanding of the transformation, for example that DOI: 10.1039/d0sc06222g environmental factors influence the stereoselectivity of glycosylations more than the coupling partners in rsc.li/chemical-science this area of chemical space. Introduction retrosynthesis,9 reaction performance10 and products,11,12 the identication of new materials and catalysts,13–15 as well as Predicting the outcome of an organic reaction generally enantioselectivity16,17 have been addressed. However, a signi- This article is licensed under a requires a detailed understanding of the steric and electronic cant challenge is predictability of reactions involving SN1or 1,2 3 18 factors inuencing the potential energy surface and inter- SN1-type mechanisms in the absence of chiral catalysts/ mediate(s).4 Quantum mechanical calculations have signi- ligands,19 due to the potentially unclear mechanistic pathways Open Access Article. Published on 26 December 2020. Downloaded 9/26/2021 6:53:11 PM. cantly increased our ability to identify and quantify these resulting from the instability of the carbocationic factors. However, the correlation of these physical properties intermediate.16,17,20 with reaction outcome becomes exceedingly challenging with Glycosylation is one of the most mechanistically complex – each increase in dimensionality (e.g., additional reaction organic transformations,20 22 where an electrophile (donor), participants, pathways). Layering onto this the additional and upon activation with a Lewis or Brønsted–Lowry Acid, is coupled oen subtle nuances impacting the regio- or stereoselectivity5 of to a nucleophile (acceptor) to form a C–O bond and a stereo- a reaction complicates proceedings. genic center. This reaction involves numerous potential tran- Machine learning is a powerful tool for chemists6,7 to identify sient cationic intermediates and conformations and can 23 patterns in complex datasets from composite libraries or high- proceed via mechanistic pathways spanning SN1toSN2. The throughput experimentation.8 Chemical challenges including stereochemical outcome is determined by numerous perma- nent (dened by the starting materials) or environmental aDepartment of Biomolecular Systems, Max-Planck-Institute of Colloids and Interfaces, factors (de ned by the selected conditions/catalyst) whose Am Muhlenberg¨ 1, 14476 Potsdam, Germany. E-mail: [email protected] degree of in uence, interdepency, and relevance is poorly 20,24,25 bFreie Universitat¨ Berlin, Institute of Chemistry and Biochemistry, Arnimallee 22, understood. A systematic assessment of these factors on 14195 Berlin, Germany a ow platform allowed for the isolated interrogation of these † Electronic supplementary information (ESI) available: Detailed experimental variables. The empirical study indicated general trends/ procedures, complete datasets, additional graphs and control studies, details inuences of these factors (Fig. 1) and hypothesized their rela- regarding automation and instrumentation. Microso Excel worksheets listing 24 of descriptors, the training set, and holdout datasets 1 and 2. Code availability: tive rankings with respect to dominance. However, a data soware available at https://github.com/DrSouravChemEng/GlyMecH. See DOI: sciences approach is required to positively identify, quantify, 10.1039/d0sc06222g and apply this knowledge for the accurate prediction of ster- ‡ These authors contributed equally to this work. eoselectivities of new coupling partners and conditions. While § Current address: Department of Chemistry, University of Connecticut, 55 N. transfer learning has been applied to machine learning models Eagleville Rd, Storrs, CT, USA. © 2021 The Author(s). Published by the Royal Society of Chemistry Chem. Sci.,2021,12,2931–2939 | 2931 View Article Online Chemical Science Edge Article Fig. 1 General representation of the potential mechanistic pathways of glycosylations leading to either the alpha (a) or beta (b) anomer of the formed C–O bond. The empirically-derived permanent and environmental factors and their influence on stereoselectivity are provided.24 for the prediction of selectivities of glycosylations (reported manual selection of descriptors – quantifying sterics/electronics between preprint and publication of this work), the stereo- – using chemical intuition32 particularly important.33 Creative Commons Attribution 3.0 Unported Licence. selectivity of couplings predicted were controlled by the C-2 acyl The training dataset is a lightly modied version of the protecting group that provide a well-established, highly repro- dataset presented in our previous work,24 removing two subsets ducible means of stereocontrol in these reactions.26 of data (variance of the residence time and nucleophile equiv- alents) and adding data for b-glucose electrophile (pS6, lines 68–74 and 101–106 of Table S1, ESI†) and three additional Results and discussion solvents (pS9, lines 238–268 of Table S1, ESI†). Two holdout Algorithm training and description of datasets datasets were experimentally generated (HD1, HD2). The rst was comprised of new electrophiles, nucleophiles, acid cata- We have trained a random forest algorithm using a dataset of This article is licensed under a lysts, and solvents. Holdout dataset 2 was comprised of exam- glycosylation reactions with a variety of stereoselective ples probing the inuence of electrophile leaving group outcomes to accurately predict the stereoselectivity of new stereochemistry. glycosylations, varying coupling partners, acid catalyst, solvents, and temperature (pS5–S9, Table 1 of ESI†). Regression- Open Access Article. Published on 26 December 2020. Downloaded 9/26/2021 6:53:11 PM. based random forest algorithms have proven powerful in Descriptor generation modeling chemical reaction performance.10,27 This algorithm Structures of all starting compounds were optimized, and DFT generates several weak models in the form of decision trees. The calculations performed at the B3LYP 6-31G(d) or B3LYP 6- nodes of each of these decision trees are generated by random 311G(d) levels of theory using SPARTAN (pS37–S49 of ESI†). The shuffling of the descriptors in the training set. The nal model lower level of theory was utilized for optimization of the elec- is an “ensemble” of a combined weighted sum of decision trees, trophile molecules due to their size, and the values obtained representing a collective decision of all individual trees that were acceptable compared to those obtained at the more generate good predictions and reduces overtting. The learning computationally expensive 6-311G(d) level of theory. The performance of the algorithm can be signicantly enhanced by maximum number of potential descriptors per model was set to hyperparameter tuning (pS35 of ESI†).28 Due to the heteroge- 18 to avoid overtting by keeping the ratio of data- neous nature of the descriptors in this work (vide infra), each points : descriptors >10 : 1.34,35 The best-performing descriptors tree was generated using the CART (classication and regres- for each participant class were determined by the accuracy of sion tree) algorithm with pruning, which does not require pre- the resultant trained models in predicting stereoselectivities of processing or normalization.29 An interaction–curvature the relevant portions of holdout dataset 1 (e.g. determining the algorithm was further utilized to reduce the selection bias of the accuracy of predicting the novel electrophiles in HD1 with split predictors of the standard CART algorithm (Fig. 2). systematic screening of electrophile descriptors). Ten descrip- A set of numerical descriptors that accurately describe the tors were identied that, along with temperature, allow for the relevant steric and electronic parameters of all reaction partic- assignment of quantied values to the relevant steric/electronic ipants – starting materials, reagents, and solvent – is key to properties of the chemicals involved. building an accurate, extrapolatable model to predict the subtle The identied descriptors,
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