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• W4225410161 abstract "•Programmable selective acylation of unprotected monoglycosides•Excellent site selectivity enabled by NHC catalysts and boronic acids•Extraordinary substrate scope for both monosaccharides and acylation partners•Concise construction of sophisticated saccharide derivatives Chemical synthesis or modification of saccharides remains a difficult challenge in modern science, posing a major hurdle to the study of saccharide-related biological processes and development of new therapeutics. The synthetic challenge is largely due to the difficulty of site-selective reactions on the many similar hydroxyl groups of saccharides. Here, we disclose a programable multilayered selectivity amplification strategy for site-selective acylation of unprotected monoglycosides and their derivatives. Through proper combinations of N-heterocyclic carbene (NHC) organic catalysts and boronic acids to introduce multiple tunable driving forces, the reactivity difference of the similar hydroxyl groups can be amplified or inverted. With our strategy, it becomes feasible to identify suitable conditions for site-selective acylation of essentially most (mono)saccharides and polyol molecules. Our study will have both fundamental and practical impacts in the broad fields ranging from chemistry to medicine. Chemical synthesis or modification of saccharides remains a major challenge largely because site-selective reactions on their many similar hydroxyl groups are difficult. The lack of efficient chemical synthetic tools has therefore become a main obstacle to understanding saccharide-related biological processes and developing saccharide-based pharmaceuticals. Here, we disclose a programmable multilayered selectivity-amplification strategy enabled by boronic acids and N-heterocyclic carbene (NHC) catalysts for site-specific acylation of unprotected monoglycosides. The boronic acids provide transient shielding on certain hydroxyl groups (while simultaneously promoting reactions of other hydroxyl units) via dynamic covalent bonds to offer the first sets of selectivity controls. The NHC catalysts provide further layers of control by mediating selective acylation of the unshielded hydroxyl moieties. Multiple activating and deactivating forces can be easily modulated to yield programmable selectivity patterns. Structurally diverse monosaccharides and their analogs can be precisely reacted with different acylating reagents, leading to quick construction of sophisticated saccharide-derived products. Chemical synthesis or modification of saccharides remains a major challenge largely because site-selective reactions on their many similar hydroxyl groups are difficult. The lack of efficient chemical synthetic tools has therefore become a main obstacle to understanding saccharide-related biological processes and developing saccharide-based pharmaceuticals. Here, we disclose a programmable multilayered selectivity-amplification strategy enabled by boronic acids and N-heterocyclic carbene (NHC) catalysts for site-specific acylation of unprotected monoglycosides. The boronic acids provide transient shielding on certain hydroxyl groups (while simultaneously promoting reactions of other hydroxyl units) via dynamic covalent bonds to offer the first sets of selectivity controls. The NHC catalysts provide further layers of control by mediating selective acylation of the unshielded hydroxyl moieties. Multiple activating and deactivating forces can be easily modulated to yield programmable selectivity patterns. Structurally diverse monosaccharides and their analogs can be precisely reacted with different acylating reagents, leading to quick construction of sophisticated saccharide-derived products. Saccharides are a major class of biomolecules involved in numerous biological activities. Saccharide derivatives and multi-hydroxyl group (polyol)-containing structures are also widely found in natural products and synthetic molecules with important functions1Seeberger P.H. Werz D.B. Synthesis and medical applications of oligosaccharides.Nature. 2007; 446: 1046-1051https://doi.org/10.1038/nature05819Crossref PubMed Scopus (624) Google Scholar, 2Bertozzi C.R. Kiessling L.L. Chemical glycobiology.Science. 2001; 291: 2357-2364https://doi.org/10.1126/science.1059820Crossref PubMed Scopus (1742) Google Scholar, 3Ernst B. Magnani J.L. From carbohydrate leads to glycomimetic drugs.Nat. Rev. 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Plant polyphenols: Chemical properties, biological activities, and synthesis.Angew. Chem. Int. Ed. 2011; 50: 586-621https://doi.org/10.1002/anie.201000044Crossref PubMed Scopus (1835) Google Scholar (Figure 1A). It has been proved that modulation of saccharides or saccharide segments can lead to therapeutic agents, such as vaccines and antibiotics, with billion-dollar commercial success.8Astronomo R.D. Burton D.R. Carbohydrate vaccines: Developing sweet solutions to sticky situations?.Nat. Rev. Drug Discov. 2010; 9: 308-324https://doi.org/10.1038/nrd3012Crossref PubMed Scopus (484) Google Scholar, 9Danishefsky S.J. Shue Y.-K. Chang M.N. Wong C.-H. Development of Globo-H cancer vaccine.Acc. Chem. Res. 2015; 48: 643-652https://doi.org/10.1021/ar5004187Crossref PubMed Scopus (157) Google Scholar, 10Křen V. Řezanka T. Sweet antibiotics - The role of glycosidic residues in antibiotic and antitumor activity and their randomization.FEMS Microbiol. Rev. 2008; 32: 858-889https://doi.org/10.1111/j.1574-6976.2008.00124.xCrossref PubMed Scopus (151) Google Scholar For example, bacterial-capsule polysaccharides attached to proteins have been a main choice for conjugated vaccines.11Jones L.H. Recent advances in the molecular design of synthetic vaccines.Nat. Chem. 2015; 7: 952-960https://doi.org/10.1038/nchem.2396Crossref PubMed Scopus (79) Google Scholar Multiple saccharide-derived small molecules, such as Empagliflozin, are among the best-selling drugs.12Kang A. Jardine M.J. SGLT2 inhibitors may offer benefit beyond diabetes.Nat. Rev. Nephrol. 2021; 17: 83-84https://doi.org/10.1038/s41581-020-00391-2Crossref PubMed Scopus (19) Google Scholar However, despite the enormous applications and potential, our understanding of saccharide-related biological processes and the development of saccharide-based pharmaceuticals remain challenging. A major obstacle lies in the lack of efficient chemical synthetic tools for access to saccharides and their derivatives. It is difficult to selectively functionalize the many hydroxyl (OH) groups present in saccharides because the reactivity differences of the various OH groups are very small. Numerous approaches from the best chemists of many generations have been designed to achieve site-selective reactions on the different OH groups of saccharides and polyol molecules. The dominant approach involves elegantly designed orthogonal protection-deprotection chemistry through typically long-step operations, as demonstrated by many pioneers, such as Wong and Danishefsky.13Cheng C.-W. Zhou Y. Pan W.-H. Dey S. Wu C.-Y. Hsu W.-L. Wong C.-H. Hierarchical and programmable one-pot synthesis of oligosaccharides.Nat. Commun. 2018; 9: 5202https://doi.org/10.1038/s41467-018-07618-8Crossref PubMed Scopus (55) Google Scholar, 14Sears P. Wong C.-H. Toward automated synthesis of oligosaccharides and glycoproteins.Science. 2001; 291: 2344-2350https://doi.org/10.1126/science.1058899Crossref PubMed Scopus (450) Google Scholar, 15Kaneko M. Li Z. Burk M. Colis L. Herzon S.B. Synthesis and biological evaluation of (2S,2′S-lomaiviticin A.J. Am. Chem. Soc. 2021; 143: 1126-1132https://doi.org/10.1021/jacs.0c11960Crossref PubMed Scopus (6) Google Scholar, 16Rose J.A. Mahapatra S. Li X. Wang C. Chen L. Swick S.M. Herzon S.B. Synthesis of the bis(cyclohexenone) core of (-)-lomaiviticin A.Chem. Sci. 2020; 11: 7462-7467https://doi.org/10.1039/d0sc02770gCrossref PubMed Scopus (5) Google Scholar, 17Hoang K.M. Lees N.R. Herzon S.B. General method for the synthesis of α- or β-deoxyaminoglycosides bearing basic nitrogen.J. Am. Chem. Soc. 2021; 143: 2777-2783https://doi.org/10.1021/jacs.0c11262Crossref PubMed Scopus (12) Google Scholar, 18Griffith D.A. Danishefsky S.J. Sulfonamidoglycosylation of glycals. A route to oligosaccharides with 2-aminohexose subunits.J. Am. Chem. Soc. 1990; 112: 5811-5819https://doi.org/10.1021/ja00171a021Crossref Scopus (202) Google Scholar, 19Deshpande P.P. Danishefsky S.J. Total synthesis of the potential anticancer vaccine KH-1 adenocarcinoma antigen.Nature. 1997; 387: 164-166https://doi.org/10.1038/387164a0Crossref PubMed Scopus (73) Google Scholar Although improvements are being made in this protection-deprotection approach, new strategies with shorter steps that avoid (or minimize) conventional protection-deprotection operations have attracted intense attention for obvious reasons. For instance, the Hanessian and Taylor groups have studied organoboron20Lee D. Williamson C.L. Chan L. Taylor M.S. Regioselective, borinic acid-catalyzed monoacylation, sulfonylation and alkylation of diols and carbohydrates: Expansion of substrate scope and mechanistic studies.J. Am. Chem. Soc. 2012; 134: 8260-8267https://doi.org/10.1021/ja302549cCrossref PubMed Scopus (166) Google Scholar,21Lee D. Taylor M.S. Borinic acid-catalyzed regioselective acylation of carbohydrate derivatives.J. Am. Chem. Soc. 2011; 133: 3724-3727https://doi.org/10.1021/ja110332rCrossref PubMed Scopus (203) Google Scholar and metal reagents (such as organotin)22David S. Hanessian S. Regioselective manipulation of hydroxyl groups via organotin derivatives.Tetrahedron. 1985; 41: 643-663https://doi.org/10.1016/S0040-4020(01)96443-9Crossref Scopus (649) Google Scholar to amplify the intrinsic selectivity of cis-1,2-diols based on the inherent reactivity differences between equatorial and axial OH groups. Blaszczyk and Tang developed a selective acylation protocol for trans-1,2-diols in S-glycosides via nicely designed chiral catalysts and an adamantyl directing group.23Blaszczyk S.A. Tang W. S-Adamantyl group directed site-selective acylation and its applications in the streamlined assembly of oligosaccharides.Angew. Chem. Int. Ed. 2019; 58: 9542-9546https://doi.org/10.1002/anie.201903587Crossref PubMed Scopus (16) Google Scholar Miller and co-workers designed small-molecule enzyme mimics for chemo- and/or stereoselective reactions of saccharides and polyols.24Fiori K.W. Puchlopek A.L.A. Miller S.J. Enantioselective sulfonylation reactions mediated by a tetrapeptide catalyst.Nat. Chem. 2009; 1: 630-634https://doi.org/10.1038/nchem.410Crossref PubMed Scopus (112) Google Scholar,25Featherston A.L. Kwon Y. Pompeo M.M. Engl O.D. Leahy D.K. Miller S.J. Catalytic asymmetric and stereodivergent oligonucleotide synthesis.Science. 2021; 371: 702-707https://doi.org/10.1126/science.abf4359Crossref PubMed Scopus (32) Google Scholar Kawabata and colleagues developed chiral pyridine-based organic catalysts that can selectively acylate OH groups at the C4-carbon of glucose.26Shibayama H. Ueda Y. Tanaka T. Kawabata T. Seven-step stereodivergent total syntheses of punicafolin and macaranganin.J. Am. Chem. Soc. 2021; 143: 1428-1434https://doi.org/10.1021/jacs.0c10714Crossref PubMed Scopus (14) Google Scholar,27Takeuchi H. Mishiro K. Ueda Y. Fujimori Y. Furuta T. Kawabata T. Total synthesis of ellagitannins through regioselective sequential functionalization of unprotected glucose.Angew. Chem. Int. Ed. 2015; 54: 6177-6180https://doi.org/10.1002/anie.201500700Crossref PubMed Scopus (70) Google Scholar Studer and co-workers found selective reactions of partially protected monosaccharides with NHC catalysts.28Cramer D.L. Bera S. Studer A. Exploring cooperative effects in oxidative NHC catalysis: Regioselective acylation of carbohydrates.Chem. Eur. J. 2016; 22: 7403-7407https://doi.org/10.1002/chem.201601398Crossref PubMed Scopus (31) Google Scholar The use of other organic or metal catalysts and reagents for site-selective reactions of saccharides with minimized protections has also been reported.29Xiao G. Cintron-Rosado G.A. Glazier D.A. Xi B.-m. Liu C. Liu P. Tang W. Catalytic site-selective acylation of carbohydrates directed by cation-n interaction.J. Am. Chem. Soc. 2017; 139: 4346-4349https://doi.org/10.1021/jacs.7b01412Crossref PubMed Scopus (66) Google Scholar, 30Li R.-Z. Tang H. Wan L. Zhang X. Fu Z. Liu J. Yang S. Jia D. Niu D. Site-divergent delivery of terminal propargyls to carbohydrates by synergistic catalysis.Chem. 2017; 3: 834-845https://doi.org/10.1016/j.chempr.2017.09.007Abstract Full Text Full Text PDF Scopus (63) Google Scholar, 31Sun X. Lee H. Lee S. Tan K.L. Catalyst recognition of cis-1,2-diols enables site-selective functionalization of complex molecules.Nat. Chem. 2013; 5: 790-795https://doi.org/10.1038/NCHEM.1726Crossref PubMed Scopus (0) Google Scholar, 32Peng P. Linseis M. Winter R.F. Schmidt R.R. Regioselective acylation of diols and triols: The cyanide effect.J. Am. Chem. Soc. 2016; 138: 6002-6009https://doi.org/10.1021/jacs.6b02454Crossref PubMed Scopus (44) Google Scholar, 33Mensah E. Camasso N. Kaplan W. Nagorny P. Chiral phosphoric acid directed regioselective acetalization of carbohydrate-derived 1,2-diols.Angew. Chem. Int. Ed. 2013; 52: 12932-12936https://doi.org/10.1002/anie.201304298Crossref PubMed Scopus (66) Google Scholar, 34Blaszczyk S.A. Homan T.C. Tang W. Recent advances in site-selective functionalization of carbohydrates mediated by organocatalysts.Carbohydr. Res. 2019; 471: 64-77https://doi.org/10.1016/j.carres.2018.11.012Crossref PubMed Scopus (35) Google Scholar, 35Dimakos V. Taylor M.S. Site-selective functionalization of hydroxyl groups in carbohydrate derivatives.Chem. Rev. 2018; 118: 11457-11517https://doi.org/10.1021/acs.chemrev.8b00442Crossref PubMed Scopus (163) Google Scholar Each of these methods has its own merits and limitations. For example, in these previous approaches, pre-protection of the C6- and/or C4-OH groups (of monosaccharides) is still necessary before selective reaction can be performed on the remaining OH units. The generality of monosaccharide partners is typically limited to those with certain structural requirements (such as the presence of cis-diols). Individual access to different sites (such as to C2-, C3-, and C6-sites individually) via each of these approaches is still difficult. Further breakthroughs in this arena of saccharide-selective reactions remain to emerge. Given the complexity of saccharides and the corresponding reacting partners, it appears that introducing more controlling parameters that can be modularly tuned could offer attractive solutions. Here, we disclose a programmable strategy mediated by multiple driving forces for site-selective acylation of unprotected monoglycosides, their analogs, and their derivatives (Figure 1B). We break down the challenging selectivity problem into a few smaller issues, each of which can be addressed by different cooperative catalysts and additives. With d-glucoside (primary alcohol group unprotected) as a model example, the use of boronic acid additive can selectively shield the two OH groups at the C4- and C6-carbons by forming a six-membered boronic ester with labile boron-oxygen bonds. This dynamic boronic ester formation temporarily protects these two OH groups from further reactions, providing the first layer of selectivity control. The introduction of boronic acid additives can also simultaneously accelerate reactions of certain OH groups,36Tang H. Tian Y.-B. Cui H. Li R.-Z. Zhang X. Niu D. Site-switchable mono-O-allylation of polyols.Nat. Commun. 2020; 11: 5681https://doi.org/10.1038/s41467-020-19348-xCrossref PubMed Scopus (15) Google Scholar offering a second layer of selectivity control. In the same reaction solution, an N-heterocyclic carbene (NHC) organic catalyst is introduced to provide a further layer of site-selectivity control. Multiple parameters involving stereo-electronic effects and covalent and/or non-covalent interactions (NCIs) brought by the boronic acids and NHC catalysts can be readily modulated. With our approach, through appropriate combined choices of boronic acids and/or NHCs, the acyl group can be site-selectively installed on the C(2)-OH, C(3)-OH, or C(6)-OH of d-glucoside. Our strategy can be easily tuned for site-specific acylation of various monosaccharides and their analogs by varying the structures of boronic acids and/or NHC catalysts (as illustrated in the left graph of Figure 1B). Sophisticated molecules (such as natural products) containing saccharide fragments can also undergo selective acylation reactions with different carboxylic acids and derivatives, including those with commercial applications as medicines (such as artesunate and dehydrocholic acid). Applications of our selective acylation strategy can allow for concise synthesis of saccharide-derived products, such as (R)-punicafolin, (S)-macaranganin,37Tanaka T. Nonaka G.I. Nishioka I. Punicafolin, an ellagitannin from the leaves of Punica granatum.Phytochemistry. 1985; 24: 2075-2078https://doi.org/10.1016/S0031-9422(00)83125-8Crossref Scopus (97) Google Scholar,38Lin J. Nonaka G.-i. Nishioka I. Tannins and related compounds. XCIV. Isolation and characterization of seven new hydrolyzable tannins from the leaves of Macaranga tanarius (L.) Muell. et Arg..Chem. Pharm. Bull. 1990; 38: 1218-1223https://doi.org/10.1248/cpb.38.1218Crossref Scopus (55) Google Scholar and disaccharide laminaribiose,39Bächli P. Percival E.G.V. 224. The synthesis of laminaribiose (3-β-D-glucosylD-glucose) and proof of its identity with laminaribiose isolated from laminarin.J. Chem. Soc. 1952; : 1243-1246https://doi.org/10.1039/JR9520001243Crossref Google Scholar with important bioactivities. Summarized in Figure 2 are key results of a model reaction (with d-glucoside [1] as the monosaccharide) from extensive studies on the effects of boronic acids, NHC catalysts, and other parameters such as bases and solvents. Further details of condition optimizations are provided in the supplemental information. The reaction and its simplified mechanistic pathway are briefly illustrated in Figure 2. A glucoside (1), acylation substrate (2a, 2b, or 2c), NHC pre-catalyst (N1, 10–20 mol %), boronic acid (B1, 100 mol %), and base (20–200 mol %) were dissolved in an organic solvent (e.g., CH3CN or EtOAc). The reaction involves reversible reactions between two OH groups (C4- and C6-OH groups) of glucoside with boronic acid to form boronic ester I as an intermediate (detectable via 1H NMR of the crude reaction mixture or isolable depending on the specific substrates; see supplemental information part 2.6).40Dimakos V. Garrett G.E. Taylor M.S. Site-selective, copper mediated O-arylation of carbohydrate derivatives.J. Am. Chem. Soc. 2017; 139: 15515-15521https://doi.org/10.1021/jacs.7b09420Crossref PubMed Scopus (44) Google Scholar, 41Tay J.-H. Dorokhov V. Wang S. Nagorny P. Regioselective single pot C3-glycosylation of strophanthidol using methylboronic acid as a transient protecting group.J. Antibiot. 2019; 72: 437-448https://doi.org/10.1038/s41429-019-0172-1Crossref PubMed Scopus (8) Google Scholar, 42Fenger T.H. Madsen R. Regioselective glycosylation of unprotected phenyl 1-thioglycopyranosides with phenylboronic acid as a transient masking group.Eur. J. Org. Chem. 2013; : 5923-5933https://doi.org/10.1002/ejoc.201300723Crossref Scopus (31) Google Scholar, 43Kaji E. Nishino T. Ishige K. Ohya Y. Shirai Y. Regioselective glycosylation of fully unprotected methyl hexopyranosides by means of transient masking of hydroxy groups with arylboronic acids.Tetrahedron Lett. 2010; 51: 1570-1573https://doi.org/10.1016/j.tetlet.2010.01.048Crossref Scopus (55) Google Scholar This dynamic boronic ester formation not only provides a transient protection of the two OH groups from subsequent acylation reactions but also assists in regulating the acylation tendency of other OH groups by variating the substituents of boronic acids. In the same reaction solution, the NHC catalyst reacts with the acylation substrate to form acyl azolium intermediate II.44Hopkinson M.N. Richter C. Schedler M. Glorius F. An overview of N-heterocyclic carbenes.Nature. 2014; 510: 485-496https://doi.org/10.1038/nature13384Crossref PubMed Scopus (2859) Google Scholar,45Chen X. Wang H. Jin Z. Chi Y.R. N-Heterocyclic carbene organocatalysis: activation modes and typical reactive intermediates.Chin. J. Chem. 2020; 38: 1167-1202https://doi.org/10.1002/cjoc.202000107Crossref Scopus (118) Google Scholar The acylation substrates in our studies (as precursors of acyl azolium intermediates) can be aldehydes (2a; in the presence of an oxidant, such as DQ), carboxylic acids (2b; in the presence of a coupling reagent, such as dicyclohexyl carbodiimide [DCC]), or carboxylic esters (2c) (Figure 2; for details, see supplemental information parts 2.3–2.5). The acylation reaction between intermediates I and II first forms an acylated boronic ester of the glucoside as adduct III (as observed via 1H NMR analysis of the crude reaction mixture). In this step (from intermediates I and II to adduct III), regioselectivity between the C(2)-OH and C(3)-OH moieties is controlled by the structures of both the NHC catalyst and the boronic acid. The boronic ester moiety of this adduct (III) then undergoes hydrolysis in the same reaction mixture or upon silica-gel column chromatography to eventually form the site-selective acylated saccharide product 3. It is worth noting that the boronic ester formation (thermodynamically favorable under the reaction condition) and hydrolysis are a facile and reversible process for both intermediates I and III (for details, see supplemental information parts 2.6 and 3.3). It is technically necessary to use a stoichiometric amount of the boronic acid to achieve optimal regioselectivity and avoid over-acylation on more than one OH group. Four sets of conditions (1A, 1B, 2A, and 3A; Figure 2) were identified to give acceptable results. We chose condition 1B to study the effects of NHC catalysts and boronic acids given that four possible mono-acylated saccharide adducts could be observable under this type of condition (CH3CN as solvent; 1 equiv of DQ and boronic acid). The loadings of boronic acid (B1) had a clear influence on the reaction yields and selectivity (Figure 3A). Increasing the loadings of boronic acid significantly increased the yield of C3-O-acylate while decreasing those of C6-O-acylate and C4-O-acylate. The yield of C2-O-acylate remained largely unchanged as the boronic acid loadings were varied. The structures of the boronic acids (as exemplified by selected examples B1–B7) also dramatically affected the yields and selectivity of the reactions (Figure 3B). For example, removing the methoxy substituents on the phenyl ring of B1 (to give boronic acid B3) led to a big drop in yields of C3-O-acylate and the ratios (selectivity) between C3-O-acylate and C2-O-acylate. The presence of boronic acid generally increased the overall acylation yields (e.g., 68% overall acylation yield with the presence of 1 equiv of B1 versus 38% overall yield without B1; Figures 3A and 3B). These results suggest that the formation of boronic ester intermediate (I; Figure 2) also simultaneously activates C(3)-OH toward acylation reactions. Such activation effects can be designed to occur on other OH groups, such as the C(2)-OH moiety, as observed in other examples of this study. The structures of NHC catalysts also showed profound effects on both reaction yields and selectivity values (Figure 3C; for details, see supplemental information part 2.7). Our results (Figures 3A–3C) clearly show that both NHCs and boronic acids have distinct effects on each of the different OH groups present in saccharides and their analogs. These effects can be deactivation (temporary shielding) or activation on different OH groups, providing amplified reactivity differentiations of these moieties. It is therefore feasible to engineer these effects in a combinatorial and programmable manner (Figures 1B, 5, and 7) to achieve site-selective acylation on different OH groups of various types of saccharides (and polyols) with diverse acylation partners. For example, selective C(2)-OH acylation of glucoside (1) could be achieved by the combined use of chiral NHC pre-catalyst N6 and boronic acid B8 under a slightly modified condition to give C2(OH)-acylated product in 63% yield and 7:1 regioselectivity (Figures 3D and 4). Acylation of C(6)-OH of glucoside (1) selectively was achieved with the NHC pre-catalyst (N4) alone (Figures 3E and 4). In other examples of this study, selective C(6)-OH acylation was obtained via the combined use of an NHC pre-catalyst and a boronic acid. We next evaluated the scope and applications of our strategy. Our condition screening in this study ended up with the use of five NHC catalysts and eight boronic acids (with 5 × 8 possible combinations) for optimal outcomes of the different types of saccharides and acylation partners. Although a definite relation between structures and reaction outcomes cannot be drawn at this point, a number of guiding trends were observed, as illustrated in Figure 4. For instance, the combination of N1 and B1 worked well for C(3)-OH acylation of α- and β-glucoside (combination 2 in Figure 4). This combination (N1 + B1) also worked effectively for similar selectivity patterns when we used carboxylic acids or esters as the acylation agents (Figure 7). We eventually identified 12 combinations of NHCs and boronic acids (combinations 1–12 in Figure 4) for various selective reactions on a large set of saccharides and acylation partners (Figures 5 and 7; for details, see supplemental information parts 2.8 and 2.9). The substrate tolerances and limitations using aldehydes as the acylation reagents were studied (Figure 5). With glucoside (1) as a model saccharide, C(3)-OH selective acylation could be achieved with various aryl aldehydes (3–17) and α,β-unsaturated aldehydes (18 and 19). The use of alkyl aldehyde gave little saccharide acylation adducts. Multiple different types of monosaccharides and their analogs could undergo selective C(3)-OH acylation as well (20–38). For example, β-glucosides and their derivatives, including a natural product (geniposide),46Wu S.-Y. Wang G.-F. Liu Z.-Q. Rao J.-J. LÜ L. Xu W. Wu S.-G. Zhang J.-J. Effect of geniposide, a hypoglycemic glucoside, on hepatic regulating enzymes in diabetic mice induced by a high-fat diet and streptozotocin.Acta Pharmacol. Sin. 2009; 30: 202-208https://doi.org/10.1038/aps.2008.17Crossref PubMed Scopus (146) Google Scholar could be selectively acylated (20–23) with 66%–75% yields and around 10:1 regioselectivity. Diabetes drugs containing analogs of monosaccharides, dapagliflozin and empagliflozin,19Deshpande P.P. Danishefsky S.J. Total synthesis of the potential anticancer vaccine KH-1 adenocarcinoma antigen.Nature. 1997; 387: 164-166https://doi.org/10.1038/387164a0Crossref PubMed Scopus (73) Google Scholar could be acylated with good yields and excellent regioselectivity (24 and 25). The C(3)-OH acylation of α- and β-galactosides was achievable with NHC N1 and boronic acid B9 (combination 5) (26–32). Examples of other monosaccharides evaluated under current conditions for C(3)-OH acylations include aminoglycoside (33), α- and β-xylopyranosides (34 and 35), mannoside (36), rhamnopyranoside (37), and glucal (38). Site-selective acylations on C(2)-OH moieties were obtained by a combination of N6 + B8 (combination 11) or N1 + B10 (combination 6) (Figure 5). Examples of saccharides that gave satisfactory yields and selectivity values for C(2)-OH acylation under current conditions include glucoside and galactosides (39–46). The C(6)-OH of various saccharides and analogs (47–60) could be selectively acylated through the sole use of an NHC catalyst (“combinations” 1, 7, and 10) or in the presence of both NHCs and boronic acids (combinations 9 and 12). For example, the C(6)-OH of α- and β-glucosides was selectively acylated by NHC pre-catalyst N4 alone (47–50). Acylation on the C(6)-OH of β-galactosides (51–55) was realized by N4 and B11 (combination 9). It is worth keeping in mind that for the same set of saccharide and acylation reagent, the use of different conditions offers dramatically different selectivity outcomes. For example, for the same aminoglycoside, the use of an NHC catalyst (N1) alone gave C(6)-OH acylation product 56, whereas a combined use of N1 and boronic acid B3 gave C(3)-OH acylation product 33. Similar comparisons can be made for other examples, such as products 3, 39, and 47 from α-glucoside (acylation on C3, C2, and C6, respectively). As a technical note, changes to both NHC catalysts and boronic acids are often needed for achieving optimal yields and selectivity values for each of the different OH groups on the same saccharides. To understand how the various interactions between the components of the reaction affect regioselective acylation, we chose five model reactions to study (Figur" @default.
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• W4225410161 title "Programmable selective acylation of saccharides mediated by carbene and boronic acid" @default.
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