MPTGs: Thioglycoside Donors for Acid-Catalyzed O‑Glycosylation and

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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MPTGs: Thioglycoside Donors for Acid-Catalyzed O‑Glycosylation and Latent-Active Synthetic Strategies Shaofu Du and Justin R. Ragains* Department of Chemistry, Louisiana State University, Baton Rouge, Louisiana 70803, United States

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S Supporting Information *

ABSTRACT: 4-(p-Methoxyphenyl)-4-pentenylthioglycosides (MPTGs) undergo acid-catalyzed O-glycosylation with a range of alcohol acceptors in the presence of 10 mol % of triflic acid at room temperature. Particularly encouraging is the reactivity of MPTGs toward unreactive acceptors. MPTGs can be synthesized from the requisite vinyl bromides using the Suzuki reaction, and this chemistry can be leveraged toward a “latent-active” strategy for oligosaccharide synthesis.

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activation occurred under relatively mild conditions at room temperature, a departure from most methods for thioglycoside activation that suggested the potential utility of MBTGs for oligosaccharide synthesis. Acid-catalyzed activation of MBTGs enabled high-yielding O-glycosylations at room temperature and provided reactivity with a greater range of “armed” and “disarmed” donors than photochemical activation.3h In addition, MBTGs proved to be stable toward weaker acids than HOTf (e.g., trifluoroacetic acid) and stable to a range of other conditions3h that are compatible with thioglycosides2c,3a−f,5 which, in turn, have proven to be a workhorse for O-glycosylation and oligosaccharide synthesis. Nevertheless, the reactivity of MBTGs toward poorly reactive alcohol acceptors remained low.3h As such, we synthesized an alternative 4-(p-methoxyphenyl)-4-pentenylthioglycoside (MPTG, 1a, Scheme 1) and demonstrated its reactivity toward a single hindered acceptor (α-methyl-2,3,6-tri-Obenzylglucoside) in our initial report on acid catalysis.3h We proposed that protonation of MPTGs (2) by acid catalyst (resulting in 3° benzylic carbocation 3) was more facile than protonation of MBTGs (resulting in a 2° benzylic carbocation), and we surmised that this increase in reactivity could translate to higher yields with hindered acceptors. In support of the mechanistic proposal in Scheme 1, we were able to isolate the heterocycle 6 from reaction mixtures.3h Herein, we demonstrate the reactivity of a range of “armed” and “disarmed” MPTGs toward a host of alcohol acceptors of varying reactivity at a 0.075 mmol scale and a single example at a 1 mmol scale. Importantly, rates of activation are reasonable regardless of the electron density at sulfur. In particular, we demonstrate moderate- to high-yielding transformations with very poorly reactive acceptors6 including the C4 hydroxyl groups of glucuronic acid, glucose, and galactose. OGlycosylations with MPTGs work well at room temperature

he microheterogeneity of oligosaccharides obtained from natural sources renders the isolation of pure samples for biochemical characterization a difficult process.1 As a result, synthesis of oligosaccharides by enzymatic2 or chemical means is necessary for the unambiguous assignment of function. In the realm of chemical synthesis, the development of effective O-glycosylation electrophiles (glycosyl donors) and mild and straightforward strategies for their activation remain important endeavors for furthering glycoscience.3 We and others have shown that remote activation strategies can be particularly effective for the activation of glycosyl donors under relatively mild conditions that leave most other functionalities unscathed.4 In particular, we recently introduced 4-(p-methoxyphenyl)-3-butenylthioglycosides (MBTGs, Scheme 1) first in the context of visible-light photochemical activation3g and later in the context of acid-catalyzed activation with trifluoromethanesulfonic acid (HOTf).3h Both modes of Scheme 1. 4-(p-Methoxyphenyl)-3-butenylthioglycosides and 4-(p-Methoxyphenyl)-4-pentenylthioglycosides

Received: December 11, 2018

© XXXX American Chemical Society

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DOI: 10.1021/acs.orglett.8b03958 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

acceptor at differing scales and dilutions provided inferior yields (entries 5−8). In addition, diminished yields were obtained with TMSOTf (entry 9). Surprisingly, attempts to perform experiments at low temperature (0 and −20 °C) provided complex mixtures with none of the expected product 8 (entries 10 and 11). Initially, we thought that poor reactivity of acceptor toward unstable intermediates at these temperatures might explain this result. However, even methanol led to similarly complex mixtures. Reasons for this outcome are poorly understood at the moment. Continuing optimization demonstrated that a full equivalent of HOTf was detrimental to the outcome (entry 12), while not surprisingly, omission of HOTf resulted in no observed conversion of 1a (entry 13). Further, screening of more polar solvents (entries 14 and 15) yielded inferior results. In addition, substitution of HOTf with trifluoroacetic acid resulted in no detected conversion of 1a (entry 16), while substitution of HOTf with HClO4 (entry 17) resulted in a complex mixture containing unreacted 7 and small amounts of 8. As such, we opted to use conditions from entry 1 for substrate scope studies. Finally, performance of this transformation at a 1 mmol scale (1 mmol 7 and 1.5 mmol 1a, see Supporting Information (SI) for details) resulted in 72% of 8. Our substrate scope studies (Scheme 2) commenced with tetrabenzoyl donor 1a and a series of secondary alcohol acceptors. α-Methyl-3,4,6-tri-O-benzylglucoside afforded 81% of the desired disaccharide (entry 1), while a galactose C4 acceptor (entry 2) and a glucuronic acid C4 acceptor (entry 3) afforded moderate yields (54% and 59%, respectively) of products. Given the exceptionally poor reactivity of these acceptors,6 we found these results to be very encouraging and indicative of the potential utility of MPTGs for the synthesis of oligosaccharides. Continuing studies with tetrabenzyl MPTG donor 1b and acceptors including the C6 acceptor α-methyl2,3,4-tri-O-benzylglucoside (entry 4), menthol (entry 5), 1adamantanol (entry 6), and cholesterol (entry 7) provided good yields (74−83%) of O-glycosylation products, while more difficult acceptors (tri-O-benzylated α-methylhexosides like those used in entries 1−3) underwent O-glycosylation to generate substantial quantities of the desired products accompanied by unidentified and inseparable impurities. The entry 7 (cholesterol) results demonstrate the compatibility of electroneutral alkenes with this method. We then synthesized 2-acetyl-3,4,6-tri-O-benzyl donor 1c and tetraacetyl donor 1d and screened them with a series of acceptors. Donor 1c provided a 68% yield of both disaccharide products 16 and 17 when reacted with the C4 and C6 hydroxyl groups of tri-O-benzyl-protected α-methyl glucoside acceptors (entries 8 and 9), a 51% yield when reacting with the 4hydroxyl of benzyl-protected α-methyl galactoside (entry 10), and a 62% yield when reacting with the 2-hydroxyl of α-methyl 3,4,6-tri-O-benzylglucoside (entry 11). As we and others have shown,3h,8 tetraacetyl-protected donors are often poorly behaved in glycosylation procedures. The tetraacetyl donor 1d was reacted with the C6 hydroxyl (entry 12) and the C4 hydroxyl (entry 13) of tri-O-benzyl-protected α-methyl glucosides. Ironically, a yield of 35% was obtained in entry 12, whereas a yield of 57% was obtained in entry 13 with the “more difficult” acceptor. It is possible that the higher yield in the case of entry 13 is due to the less reactive C4 hydroxyl being more selective toward the anomeric center of the activated donor than the C6 hydroxyl in entry 12.

and are operatively straightforward. Like MBTGs, activation of MPTGs with catalytic acid renders them compatible with electroneutral alkenes, which is unusual for thioglycoside activation.3a,b Perhaps most importantly, the structure of MPTGs suggested a latent-active synthetic strategy (negating concerns about a lack of differential reactivity among donors with varying electron density at sulfur) that we put into action with the synthesis of a model trisaccharide. This latent-active strategy contributes to a growing arsenal of related methods in the area of O-glycosylation.5c,7 Our initial development of MPTGs had not been subjected to optimization,3h so we opted to look at the effects of various parameters including concentration, ratio of MPTG/acceptor, temperature, acid catalyst, and solvent using MPTG donor 1a. As our initial report3h demonstrated near-quantitative yields with the 6-position of methyl glucoside, we elected to pursue optimization with the less reactive 4-position of methyl glucoside using the acceptor α-methyl-2,3,6-tri-O-benzylglucoside (7, Table 1). Table 1. Optimizationa

entry

1 (mmol)

7 (mmol)

solvent

rxn temp (°C)

yieldb (%)

1 2 3 4 5 6 7 8 9c 10 11 12 13 14 15 16d 17e

0.15 0.15 0.15 0.38 0.075 0.075 0.1 0.12 0.15 0.15 0.15 0.15 0.15 0.15 0.15 0.15 0.15

0.075 0.075 0.075 0.19 0.075 0.075 0.1 0.1 0.075 0.075 0.075 0.075 0.075 0.075 0.075 0.075 0.075

CH2Cl2 CH2Cl2 (2 mL) CH2Cl2 (10 mL) CH2Cl2 CH2Cl2 CH2Cl2 (2 mL) CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH3CN acetone CH2Cl2 CH2Cl2

20 20 20 20 20 20 20 20 20 0 −20 20 20 20 20 20 20

70 70 45 63 43 37 44 46 58 n.d. nd trace nd nd nd nd n/a

a

Unless otherwise stated, the indicated amounts of donor 1a and acceptor 7 were magnetically stirred with the indicated solvent (1 mL unless explicitly stated (e.g., “CH2Cl2 (10 mL)” under the “solvent” heading)) and 10 mol % of HOTf (relative to donor) at the indicated temperature for 3 h. bIsolated yields. cUsed 10 mol % of TMSOTf instead of HOTf. dUsed trifluoroacetic acid instead of HOTf. eUsed 70% HClO4 instead of HOTf; nd, no product 8 detected; n/a, not applicable/purification not performed.

Our initial studies of concentration demonstrated that 0.075 mmol of acceptor 7 with 0.15 mmol of tetrabenzoyl donor 1a and 10 mol % of HOTf could provide high yields of disaccharide 8 at 20 °C in either 1 or 2 mL of CH2Cl2 (70%, entries 1 and 2) but that further dilution (45%, 10 mL of CH2Cl2) had a negative effect on yield (entry 3). Further, while increasing the concentration of donor and acceptor in 1 mL of CH2Cl2 had, at best, a minor effect on yield (63%, entry 4), various attempts at using a ∼1:1 ratio of donor and B

DOI: 10.1021/acs.orglett.8b03958 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 2. Substrate Scopea

Scheme 3. Latent-Active Strategy

a

Unless otherwise stated, 0.15 mmol of MPTG donor and 0.075 mmol of alcohol acceptor were used along with 10 mol % (relative to donor) of HOTf and 1 mL of CH2Cl2 and the mixture stirred at 20 °C for 70 min or until alcohol had been consumed according to TLC analysis. Then 20 mol % of Et3N (relative to donor) was added. After evaporation, products were purified by silica gel chromatography and yields of isolated products were determined.

demonstrating the potential efficacy of our “latent-active” approach in the synthesis of complex targets. In conclusion, we have demonstrated the efficacy of MPTGs as donors in a range of O-glycosylation reactions. Reactions are performed at room temperature, and high yields can be obtained in the absence of molecular sieves. Further, we have shown that the requisite latent vinyl bromide-bearing donors can be converted to the active MPTGs via Suzuki coupling and that this strategy could be applied toward the synthesis of a model trisaccharide. Because of their reactivity toward unreactive donors under user-friendly conditions and their applicability toward “latent-active” strategies, we believe that MPTGs are suitable for the synthesis of complex oligosaccharides. Such studies are currently underway in our laboratory.

With the establishment of substrate scope, we next pursued a latent-active O-glycosylation exploiting structural features of MPTGs. We noted that Pd-catalyzed cross-coupling could potentially be used to establish the bond between the sidechain alkene and the side-chain p-methoxyphenyl group of MPTGs. We also surmised that the requisite vinyl halidebearing thioglycosides would be less reactive toward protonation than MPTGs. As a proof of concept (Scheme 3), we synthesized vinyl bromide-bearing thioglycoside 22 and demonstrated its poor reactivity toward our standard conditions for MPTG activation (eq 1), establishing 22 as a latent donor. Then 22 was subjected to Suzuki coupling with p-methoxyphenylboronic acid (eq 2) to generate the active MPTG donor. We were especially pleased with this result given the potentially deleterious role of sulfur in Pd-catalyzed cross-coupling reactions. Given the aforementioned successes, we put our latentactive strategy into action (Scheme 3) with the synthesis of a model trisaccharide. Coupling of MPTG 1a with latent thioglycoside acceptor 23 resulted in a 78% yield of “latent” disaccharide 24. Subsequent Suzuki coupling of 24 with pmethoxyphenylboronic acid afforded “active” donor 25. OGlycosylation of α-methyl 2,3,4-tri-O-benzylglucoside with an excess of 25 subsequently afforded 75% of trisaccharide 26,

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03958. Experimental procedures, characterization data, 1H and 13 C NMR spectra (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Justin R. Ragains: 0000-0002-2521-5396 C

DOI: 10.1021/acs.orglett.8b03958 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Notes

(8) Kondo, H.; Aoki, S.; Ichikawa, Y.; Halcomb, R. L.; Ritzen, H.; Wong, C.-H. J. Org. Chem. 1994, 59, 864.

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We acknowledge the National Science Foundation (CHE1665208) and Louisiana State University (LSU) for generous support of this research. We thank Ms. Connie David (LSU) for assistance with high-resolution mass spectrometry.

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REFERENCES

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DOI: 10.1021/acs.orglett.8b03958 Org. Lett. XXXX, XXX, XXX−XXX