Letter pubs.acs.org/OrgLett
Pentavalent Bismuth as a Universal Promoter for S‑Containing Glycosyl Donors with a Thiol Additive Daniel E. K. Kabotso and Nicola L. B. Pohl* Department of Chemistry, Indiana University, 120A Simon Hall, 212 South Hawthorne Drive, Bloomington, Indiana 47405, United States S Supporting Information *
ABSTRACT: S-Propyl glycosides of less activated sugars, such as peracetylated carbohydrates and uronic acid esters that could not previously be activated with triphenylbismuth ditriflate alone, were found to be glycosylated in the presence of propanethiol as an additive in under 3 h. This newly developed protocol was also found to be effective in promoting glycosylation of neutral and uronic acid esters of S-phenyl, Sthiazolinyl, S-benzoxazolyl, and S-adamantyl glycosides as well as sialic acid.
S
ince their introduction in 1909,1 thioglycosides have proven to be versatile building blocks for the construction of various oligosaccharides,2−5 including in one-pot6−16 and automated/machine-assisted strategies.17 Thioglycosides have a long shelf life but can be activated when needed using a variety of promoters,18 including iodonium salts.19 However, these thiophilic promoters are generally incompatible with alkenes and/or alkynes, thereby limiting the use of these common handles in synthetic schemes. Gold trichloride 20 and triphenylbismuth ditriflate (1)21−23 have been shown to tolerate double bondsand triple bonds23 in the case of the bismuth reagentbut both reagents still have issues that limit their use. For example, gold trichloride is very hygroscopic, and the pentavalent bismuth promoter, although easily handled in air, is slow to activate sugars with many electron-withdrawing groups. For use in machine-assisted multistep synthesis, glycosylation reactions would ideally be complete within 3 h. In addition, one set of conditions needs to work with a range of substrates, as the requirement to optimize every reaction would obliterate many of the benefits of automation. Herein we report the discovery that the addition of a thiol additive accelerates triphenylbismuth ditriflate-mediated glycosylation reactions, thereby bringing reactions with uronic acids and peracetylated substrates into a 3 h time frame. In addition, this combination of reagents also allows the activation of S-phenyl, S-thiazolinyl, S-benzoxazolyl, and S-adamantyl glycosides. Triphenylbismuth ditriflate is shelf stable without use of a glovebox and is soluble in a variety of organic solvents such as dichloromethane, thereby making it compatible with automated liquid handling platforms.17 The pentavalent-bismuth-derived protocol successfully activates propyl thioglycosides of armed and disarmed neutral donors.23 However, in the case of disarmed donors such as acetylated S-phenyl galactoside 2 (Scheme 1A), the reaction is very slow, taking hours for conversion to occur. Moreover, aryl thioglycosides, aryl- and propyl thioglycosides of uronic acid esters, and those of sialic © 2017 American Chemical Society
Scheme 1. Pentavalent-Bismuth-Mediated Glycosylation of a Disarmed Peracetylated Galactose (A) without and (B) with PrSH
acids could not be activated even in an overnight time frame at ambient temperature. These disarmed thioglycoside donors are known to undergo slow activation24−26 and therefore require different protocols for more rapid activation. Recent mechanistic studies of these pentavalent-bismuthmediated glycosylations of alkyl thioglycosides showed that these reactions undergo an initial lag phase.22 Interestingly, this lag phase can be shortened with the addition of a propanethiol additive, which dramatically increases the rate of glycosylation.27 Indeed, the recalcitrant reaction with S-acetylated galactoside 2 proved feasible with the addition of propanethiol to the reaction mixture to provide the fluorous-tagged compound 4 (Scheme 1B). Given this promising initial result, a variety of substrates containing electron-withdrawing groups were probed to test whether this acceleration in rate could also possibly bring more disarmed substrates into the realm of a 3 h reaction time frame for automated synthesis protocols. Of particular interest was whether the new protocol might also activate thioglycosides Received: July 8, 2017 Published: August 15, 2017 4516
DOI: 10.1021/acs.orglett.7b02080 Org. Lett. 2017, 19, 4516−4519
Letter
Organic Letters other than the simple S-propyl and S-phenyl glycosides and activate uronic and sialic acids. To assess the potential of this new glycosylation strategy to activate a variety of thioglycoside donors, we synthesized a variety of donors containing S-phenyl, 28 S-thiazolinyl (STaz),29,30 S-benzoxazolyl (SBox),29,30 and S-adamantyl (SAda)31 groups at the anomeric carbon. In addition to sugar alcohols, alkene-, benzyl-, and hydroquinone-modified alcohols designed for fluorous solid-phase extraction (FSPE) were used as nucleophiles or glycosyl acceptors. The success of the fluorous-tagged alcohol acceptors would also make the pentavalent-bismuth-promoted glycosylation protocol amenable to our automated solution-phase synthesizer platform. The pentavalent-bismuth-mediated glycosylation reactions were conducted by adding a solution of the acceptor and propanethiol additive in anhydrous dichloromethane to a flask charged with a magnetic stirrer, the donor, and the pentavalent bismuth promoter under an argon atmosphere. The reactions were carried out at ambient temperature (23−25 °C) without the addition of molecular sieves, which are illtolerated on a liquid handling platform. A change in the color of the reaction mixture was observed immediately upon the addition of the solution of the acceptor and propanethiol additive. The new pentavalent bismuth activation protocol proved successful in activating these thioglycosides in appreciable yields ranging from 61 to 85% (Scheme 2). The reactions are fastest with the armed donor 7 (Scheme 2). On the other hand, as expected, the reactions were slower with disarmed substrates. Moreover, the reactions of S-thiazolinyl, Sbenzoxazolyl, and S-adamantyl glycosides with their corresponding coupling partners were slower, taking 2−5 h for the acceptor to completely disappear as monitored by thin-layer chromatography. By contrast, the S-alkyl glycosides could react within 90 min, depending on the nature of the protecting groups on the donor or the acceptor, thereby placing all of these reactions within a reasonable time frame for an iterative automated synthesis protocol. As expected,23 no reaction was observed with propanethiol and 2 equiv of triflic acid replacing the pentavalent bismuth promoter; the addition of 2,6-di-tertbutyl-4-methylpyridine (DTBMP)which is known to be nucleophilic32to the bismuth protocol resulted in recovered starting materials (see the Supporting Information for details). Additional mechanistic studies of the role of propanethiol in the reaction are ongoing. Given the success with a variety of glycosyl donors containing electron-withdrawing protecting groups, we next turned to uronic acids. Generally, the C-5 carboxylate ester has the property of withdrawing electron density from the sugar ring and altering the relative stability of anomers. 33 Consequently, thioglycosides of uronic acid esters are often poor donors in glycosylation reactions.34−38 Fortunately, the propanethiol/bismuth promoter combination also proved effective in carrying out glycosylation reactions of benzoylated galacturonic and glucuronic acids in reasonable yields and time frames amenable to multistep automation without any change in the protocol (Scheme 3). The new reagent combination can activate a wider range of glycosyl donors but also still keeps alkenes intact (Schemes 3 and 4). Finally, sialic acid donors were tested for their ability to undergo effective glycosylation reactions via the new protocol. Sialic acids are known to be challenging to activate because of the carboxylate substituent at the anomeric position and the lack of a substituent at C-3.39,40 The carboxylate group directly
Scheme 2. Pentavalent-Bismuth-Mediated Glycosylation Reactions of Various Thioglycosides of Neutral Sugars
attached to the anomeric center destabilizes the formation of an oxocarbenium intermediate via an inductive electron-withdrawing effect.39,40 The lack of a C-3 substituent combined with the steric strain at the anomeric center due to the carboxylate group encourages the formation of undesired elimination products.41 The lack of the neighboring group at C-3 also accounts for the poor stereoselectivity generally observed in the glycosylation outcomes of sialic acids.41 Acetylated versions of S-propyl and S-phenyl glycosides of sialic acid were synthesized and subjected to the standard protocol (Scheme 4). The anomeric configuration of the resulting product 22 was ascertained on the basis of the coupling pattern of C-1 in the gated proton-decoupled NMR experiment, as reported for all 4517
DOI: 10.1021/acs.orglett.7b02080 Org. Lett. 2017, 19, 4516−4519
Organic Letters
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Scheme 3. Pentavalent-Bismuth-Mediated Glycosylation of Thioglycosides of Uronic Acids
Letter
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02080. Synthetic protocols and characterization data, including NMR spectra, for all new compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Nicola L. B. Pohl: 0000-0001-7747-8983 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This material is based in part upon work supported by the National Science Foundation under CHE-1362213. The authors acknowledge Dr. X. Gao of the NMR Facility and M. Hansen of the Mass Spectrometry Facility at Indiana University for their help and the Joan and Marvin Carmack Chair funds for partial support of this work. We also thank Dr. M. Goswami for helpful feedback on the manuscript and Dr. R. Saliba for his help in analyzing the stereochemistry of the glycosylated products.
Scheme 4. Pentavalent-Bismuth-Mediated Glycosylation of Thioglycosides of Sialic Acid Derivatives
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