Minisci反应预测模型与氟代环丙烷化反应研究

Minisci反应能够直接向含氮杂芳环引入各种取代基，因此被广泛应用于药物分子的合成和结构修饰中。然而Minisci反应条件众多，反应结果受到多反应变量的协同影响，导致不同底物有不同的最优条件。此外，可应用的自由基前体较少，在药物研发中应用价值较大的的环丙烷，特别是光学纯的含氟环丙烷自由基前体的类型很少，且价格昂贵。针对以上不足，本论文进行了将高通量技术和机器学习应用于Minisci反应预测模型和开发光学纯的含氟环丙烷自由基前体的研究中，具体包括以下内容：

（1）通过结合高通量技术和机器学习，利用羧酸化合物作为Minisci反应自由基前体，实现了一系列的Minisci反应条件筛选和数据收集，并构建了Minisci反应预测模型。五折交叉验证时，该预测模型各种评估指标较为良好，R²=0.89，MAE=1.60%，RMSE=6.0%。

（2）发展了过渡金属催化的重氮与氟代烯烃的不对称环丙烷化反应。将高通量实验技术和人工智能有机结合，利用聚类分析和常量结合高通量实验的手段加速了光学纯的含氟环丙烷自由基前体探索历程，合成了30个光学纯的含氟环丙烷化合物。所发展的铜/手性噁唑啉催化重氮与α-氟代烯烃的不对称环丙烷化反应达到89%产率、大于20：1的dr和99%的ee值，该体系还能够很好的兼容α-氟代烷基烯烃。此外，我们还首次实现了β-氟代烯烃作为氟源的不对称环丙烷化反应，铑催化下的β-氟代烯烃与DonorAcceptor类型重氮的不对称环丙烷化反应达到99%产率、大于20：1的dr和98%的ee值，还发展了铜/手性噁唑啉催化重氮与β-氟代烯烃的不对称环丙烷化反应，反应表现出大于20：1的dr、98%的ee值和中等的产率。

[1] BHUTANI P, JOSHI G, RAJA N, et al. U.S. FDA Approved Drugs from 2015-June 2020: A Perspective[J]. Journal of Medicinal Chemistry, 2021, 64: 2339-2381.
[2] MINISCI F, BERNARDI R, BERTINI F, et al. Nucleophilic character of alkyl radicals-VI[J]. Tetrahedron, 1971, 27: 3575-3579.
[3] DOLL M K. A Short Synthesis of the 8-Azaergoline Ring System by Intramolecular Tandem Decarboxylation−Cyclization of the Minisci-Type Reaction[J]. The Journal of Organic Chemistry, 1999, 64(4): 1372-1374.
[4] CARLING R W, MADIN A, GUIBLIN A, et al. 7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4- triazol-3-ylmethoxy)-3-(2-fluorophenyl)- 1,2,4-triazolo
[4,3-b]pyridazine:  A Functionally Selective γ-Aminobutyric AcidA (GABAA) α2/α3-Subtype Selective Agonist That Exhibits Potent Anxiolytic Activity but Is Not Sedating in Animal Models [J]. Journal of Medicinal Chemistry, 2005, 48: 7089-7092.
[5] MONGA V, MEENA C L, KAUR N, et al. Facile synthesis of N-α-boc-1,2-dialkyl-l-histidines: Utility in the synthesis of thyrotropin-releasing hormone (trh) analogs and evaluation of the cns activity [J]. Journal of Heterocyclic Chemistry, 2008, 45: 1603-1608.
[6] SAWADA, OKAJIMA. Synthesis and antitumor activity of 20(S)-camptothecin derivatives: carbamate-linked, water-soluble derivatives of 7-ethyl-10-hydroxycamptothecin.[J]. Chem. Pharm. Bull., 1991, 10: 1446-1450.
[7] ZAHRT A F, HENLE J J, ROSE B T, et al. Prediction of higher-selectivity catalysts by computer-driven workflow and machine learning[J]. Science, 2019, 363: 247-247.
[8] AHNEMAN D T, ESTRADA J G, LIN S, et al. Predicting reaction performance in C–N cross-coupling using machine learning[J]. Science, 2018, 360: 186-190.
[9] MOON S, CHATTERJEE S, SEEBERGER P H, et al. Predicting glycosylation stereoselectivity using machine learning[J]. Chemical Science, 2020, 12: 2931-2939.
[10] FRANCOIS-LAVET V, HENDERSON P, ISLAM R, et al. An Introduction to Deep Reinforcement Learning[J]. Foundations and Trends® in Machine Learning, 2018, 11: 219-354.
[11] LIU Y, YANG Q, LI Y, et al. Application of Machine Learning in Organic Chemistry[J]. Chinese Journal of Organic Chemistry, 2020, 40: 3812-3812.
[12] BAIRD S G, SPARKS T D. What is a minimal working example for a self-driving laboratory?[J]. Matter, 2022, 5: 4170-4178.
[13] TAYLOR C J, FELTON K C, WIGH D, et al. Accelerated Chemical Reaction Optimization Using Multi-Task Learning[J]. Acs Central Science, 2023, 9: 957-968.
[14] DAVIES I W. The digitization of organic synthesis[J]. Nature, 2019, 570: 175-181.
[15] JI Y, BRUECKL T, BAXTER R D, et al. Innate C-H trifluoromethylation of heterocycles[J]. Proceedings of the National Academy of Sciences, 2011, 108(35): 14411-14415.
[16] COWDEN C J. Use of N-Protected Amino Acids in the Minisci Radical Alkylation[J]. Organic Letters, 2003, 5: 4497-4499.
[17] KAN J, HUANG S, LIN J, et al. Silver‐Catalyzed Arylation of (Hetero)arenes by Oxidative Decarboxylation of Aromatic Carboxylic Acids[J]. Angewandte Chemie, 2014, 127: 2227-2231.
[18] ZHAO W, CHEN X, YUAN J, et al. Silver catalyzed decarboxylative direct C2-alkylation of benzothiazoles with carboxylic acids[J]. Chemical Communications, 2014, 50: 2018-2020.
[19] MAI D N, BAXTER R D. Unprotected Amino Acids as Stable Radical Precursors for Heterocycle C–H Functionalization[J]. Organic Letters, 2016, 18: 3738-3741.
[20] GALLOWAY J D, MAI D N, BAXTER R D. Silver-Catalyzed Minisci Reactions Using Selectfluor as a Mild Oxidant[J]. Organic Letters, 2017, 19: 5772-5775.
[21] SUTHERLAND D R, VEGUILLAS M, OATES C L, et al. Metal-, Photocatalyst-, and Light-Free, Late-Stage C–H Alkylation of Heteroarenes and 1,4-Quinones Using Carboxylic Acids[J]. Organic Letters, 2018, 20: 6863-6867.
[22] REN P, SALIHU I, SCOPELLITI R, et al. Copper-Catalyzed Alkylation of Benzoxazoles with Secondary Alkyl Halides[J]. Organic Letters, 2012, 14: 1748-1751.
[23] XIAO B, LIU Z, LIU L, et al. Palladium-Catalyzed C–H Activation/Cross-Coupling of Pyridine N-Oxides with Nonactivated Secondary Alkyl Bromides [J]. Journal of the American Chemical Society, 2013, 135: 616-619.
[24] WU X, SEE J W T, XU K, et al. A General Palladium‐Catalyzed Method for Alkylation of Heteroarenes Using Secondary and Tertiary Alkyl Halides[J]. Angewandte Chemie, 2014, 126: 13791-13795.
[25] DONG J, LYU X, WANG Z, et al. Visible-light-mediated Minisci C–H alkylation of heteroarenes with unactivated alkyl halides using O2 as an oxidant[J]. Chemical Science, 2018, 10: 976-982.
[26] MOLANDER G A, COLOMBEL V, BRAZ V A. Direct Alkylation of Heteroaryls Using Potassium Alkyl- and Alkoxymethyltrifluoroborates[J]. Organic Letters, 2011, 13: 1852-1855.
[27] SEIPLE I B, SU S, RODRIGUEZ R A, et al. Direct C−H Arylation of Electron-Deficient Heterocycles with Arylboronic Acids[J]. Journal of the American Chemical Society, 2010, 132: 13194-13196.
[28] ZHANG L, LIU Z. Molecular Oxygen-Mediated Minisci-Type Radical Alkylation of Heteroarenes with Boronic Acids[J]. Organic Letters, 2017, 19: 6594-6597.
[29] MCCARTHY J, MINSKY M L, ROCHESTER N, et al. A Proposal for the Dartmouth Summer Research Project on Artificial Intelligence[J]. Ai Magazine, 2006, 27(4): 12-14.
[30] ASAHARA R, MIYAO T. Extended Connectivity Fingerprints as a Chemical Reaction Representation for Enantioselective Organophosphorus-Catalyzed Asymmetric Reaction Prediction[J]. Acs Omega, 2022, 7: 26952-26964.
[31] YANG J, CAI Y, ZHAO K, et al. Concepts and applications of chemical fingerprint for hit and lead screening[J]. Drug Discovery Today, 2022, 27: 103356-103372.
[32] MOSKAL M, BEKER W, SZYMKUć S, et al. Scaffold‐Directed Face Selectivity Machine‐Learned from Vectors of Non‐covalent Interactions[J]. Angewandte Chemie International Edition, 2021, 60: 15230-15235.
[33] QIU J, XIE J, SU S, et al. Selective functionalization of hindered meta-C–H bond of o-alkylaryl ketones promoted by automation and deep learning[J]. Chem, 2022, 8: 3275-3287.
[34] QIU J, XU Y, SU S, et al. Auto Machine Learning Assisted Preparation of Carboxylic Acid by TEMPO-Catalyzed Primary Alcohol Oxidation [J]. Chinese Journal of Chemistry, 2022, 41: 143-150.
[35] SANTANILLA A B, REGALADO E L, PEREIRA T, et al. Nanomole-scale high-throughput chemistry for the synthesis of complex molecules[J]. Science, 2014, 347: 49-53.
[36] GESMUNDO N J,SAUVAGNAT B,CURRAN P J, et al. Nanoscale synthesis and affinity ranking[J]. Nature, 2018, 557: 228-232.
[37] DAVIES I W. The digitization of organic synthesis[J]. Nature, 2019, 570: 175-181.
[38] PERERA D,TUCKER J W,BRAHMBHATT S, et al. A platform for automated nanomole-scale reaction screening and micromole-scale synthesis in flow[J]. Science, 2018, 359: 429-434.
[39] ICHIISHI N, MOORE K P, WASSERMANN A M, et al. Reducing Limitation in Probe Design: The Development of a Diazirine-Compatible Suzuki–Miyaura Cross Coupling Reaction[J]. Acs Medicinal Chemistry Letters, 2018, 10: 56-61.
[40] LEE G M, LOECHTEFELD R, MENSSEN R, et al. Synthesis of bromodifluoromethyl(arylsulfonyl) compounds and microwave-assisted nickel catalyzed cross coupling with arylboronic acids[J]. Tetrahedron Lett., 2016, 5464-5468.
[41] GESMUNDO N J, SAUVAGNAT B, CURRAN P J, et al. Nanoscale synthesis and affinity ranking[J]. Nature, 2018, 557: 228-232.
[42] PERERA D, TUCKER J W, BRAHMBHATT S, et al. A platform for automated nanomole-scale reaction screening and micromole-scale synthesis in flow[J]. Science, 2018, 359: 429-434.
[43] KING-SMITH E, FABER F A, REILLY U, et al. Predictive Minisci late stage functionalization with transfer learning[J]. Nature Communications, 2024, 15: 426-439.
[44] NIPPA D F, ATZ K, MüLLER A T, et al. Identifying opportunities for late-stage C-H alkylation with high-throughput experimentation and in silico reaction screening[J]. Communications Chemistry, 2023, 6: 256-267.
[45] BREIMAN L. Random Forests[J]. Machine Learning, 2001, 45: 5-32.
[46] GUESTRIN T C A C. XGBoost: A Scalable Tree Boosting System[J]. Association for Computing Machinery, 2016: 785-794.
[47] FRIEDMAN J H. Stochastic gradient boosting[J]. Computational Statistics & Data Analysis, 2002, 38: 367-378.
[48] SANDFORT F, STRIETH-KALTHOFF F, KüHNEMUND M, et al. A Structure-Based Platform for Predicting Chemical Reactivity[J]. Chem, 2020, 6: 1379-1390.
[49] MEANWELL N A. Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design[J]. Journal of Medicinal Chemistry, 2018, 61: 5822-5880.
[50] PINKERTON A B, PEDDIBHOTLA S, YAMAMOTO F, et al. Discovery of β-Arrestin Biased, Orally Bioavailable, and CNS Penetrant Neurotensin Receptor 1 (NTR1) Allosteric Modulators[J]. Journal of Medicinal Chemistry, 2019, 62: 8357-8363.
[51] YE S, YOSHIDA S, FRöHLICH R, et al. Fluorinated phenylcyclopropylamines. Part 4: effects of aryl substituents and stereochemistry on the inhibition of monoamine oxidases by 1-aryl-2-fluoro-cyclopropylamines.[J]. Bioorganic & Medicinal Chemistry, 2005, 13: 2489-2499.
[52] SHEN X, ZHANG W, ZHANG L, et al. Berichtigung: Enantioselective Synthesis of Cyclopropanes That Contain Fluorinated Tertiary Stereogenic Carbon Centers: A Chiral α‐Fluoro Carbanion Strategy[J]. Angewandte Chemie, 2012, 125: 508-508.
[53] BEAULIEU L B, SCHNEIDER J F, CHARETTE A B. Highly Enantioselective Simmons–Smith Fluorocyclopropanation of Allylic Alcohols via the Halogen Scrambling Strategy of Zinc Carbenoids[J]. Journal of the American Chemical Society, 2013, 135: 7819-7822.
[54] MEYER O G J, FRöHLICH R, HAUFE G. Asymmetric Cyclopropanation of Vinyl Fluorides: Access to Enantiopure Monofluorinated Cyclopropane Carboxylates[J]. Synthesis, 2000, 2000: 1479-1490.
[55] HRUSCHKA S, FRöHLICH R, KIRSCH P, et al. Synthesis of New Enantiopure Fluorinated Phenylcyclopropanecarboxylates – Potential Chiral Dopants for Liquid‐Crystal Compositions[J]. European Journal of Organic Chemistry, 2007, 2007: 141-148.
[56] SU Y, BAI M, QIAO J, et al. Diastereo- and enantioselective cyclopropanation of alkyenyl fluorides with benzyl diazoarylacetates[J]. Tetrahedron Letters, 2015, 56: 1805-1807.
[57] ADOLFSSON A,ACKERMAN M,BROWNSTEIN N C. To cluster, or not to cluster: An analysis of clusterability methods[J]. Pattern Recognition, 2019, 88: 13-26.
[58] WEI B, SHARLAND J C, LIN P, et al. In Situ Kinetic Studies of Rh(II)-Catalyzed Asymmetric Cyclopropanation with Low Catalyst Loadings[J]. Acs Catalysis, 2019, 10: 1161-1170.
[59] DAVIES H M L, BECKWITH R E J. Catalytic Enantioselective C−H Activation by Means of Metal−Carbenoid-Induced C−H Insertion[J]. Chemical Reviews, 2003, 103: 2861-2904.