Silylium (R3Si+) Catalyzed Condensative Cyclization for

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Silylium (RSi) catalyzed condensative cyclization for anhydrosugar synthesis Youngran Seo, and Michel R Gagné ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b01666 • Publication Date (Web): 15 Jun 2018 Downloaded from http://pubs.acs.org on June 18, 2018

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ACS Catalysis

Silylium (R3Si+) Catalyzed Condensative Cyclization for Anhydrosugar Synthesis Youngran Seo1, Michel R. Gagné*1 1

Department of Chemistry, The University of North Carolina at Chapel Hill, North Carolina

27599, United States ABSTRACT: The silylium (Me2EtSi+) catalyzed condensative cyclization of persilylated linear or cyclic sugars has been examined as a selective route to mono-anhydrous sugars. The silylium could be generated either from the sequential addition of [Ph3C+][B(C6F5)4–] and R3SiH or by abstracting a primary silyl ether with the Lewis acid catalyst B(C6F5)3. This latter method forms [R3SiO−B(C6F5)3–] and a silylium-coordinated product. This reactive pair eventually converts to L−B(C6F5)3 (L= THF-like product) and the condensate (R3Si)2O. The L-B(C6F5)3 is a much less potent form of the catalyst. Under the silylium catalyzed conditions, linear sugars (CnOn, n= 5, 6) and biomass-derived tetraols (C6O4) afford a diverse collection of diastereomerically pure THFs in good to excellent yields (50-99%). Persilylated 1,6-anhydrogalactofuranose is provided in a single step from persilylated galactose (85% isolation yield after silyl deprotection) and the corresponding 1,6-anhydroglucoses are available from mono-, di-, tri and oligo-gluco-

saccharides.

ACS Paragon Plus Environment

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KEYWORDS:

B(C6F5)3,

silylium,

condensative

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cyclization,

1,4-anhydrosugars,

1,6-

anhydrogalactofuranose, 1,6-anhydroglucofuranose

INTRODUCTION Dihydroxy-tetrahydrofuran (THF) units are frequently found in bioactive natural products, including (+)-varitriol,1 tiazofurin,2 and goniothalesdiol,3 which contain cis- or trans-3,4dihydroxy-THF subunits and show antitumor or antiviral activities (Figure 1). Fuzinoside4,5 consists of two 1,4-anhydrogalactitols and has potent cardiotonic effects, while the natural squalene synthase inhibitor zaragozic acid A possesses 1,6-anhydrogalactofuranose as its core structure.6 In addition to bioactive molecules, sugar biomass-derived dihydroxy-THFs are of interest as monomers for functional polymers, surfactants, or food additives.7–9 For example, 1,4anhydro-sorbitol can be converted to isosorbide (1,4;3,6-dianhydrosorbitol), which has been proposed as an alternative to a number of petroleum based compounds.7,10–12 1,6-Anhydrohexofuranoses from glucose, galactose and mannose have also been polymerized to hyperbranched polysaccharides that can be used as a carrier for a drug delivery or as stationary phase for lectin chromatography.13

Figure 1. Bioactive natural products and sugar-derived compounds containing the dihydroxy tetrahydrofuran (THF) unit.


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The general approaches for the synthesis of dihydroxy-THFs can be classified into acidic dehydration,14–17 intramolecular cyclization,18,19 or pyrolysis of saccharides.20–22 Acidic dehydration has been extensively studied with Brønsted, Lewis or heterogeneous acid catalysts to increase selectivity (1,4-anhydrosugar vs. 2,5-/or 1,5-anhydrosugar) as well as to avoid polymerization or degradation. However, the dehydration methods generally struggle with selectivities or side reactions (Scheme 1(a)).7 Other approaches include intramolecular cyclizations initiated by alkene activation (e.g. halonium or epoxidation (Scheme 1(b)),23,24 or from orthogonally O-benzyl-protected polyols (Scheme 1(c)).25–27 Although the latter routes are multi-step, they provide high selectivities, and are applicable to linear sugars (hexitols and pentitols), and galactose, which is converted to the bicyclic 1,6-anhydrogalactofuranose.28 Lewis acids in combination with microwave irradiation are also effective but need high temperatures (100 °C) (Scheme 1d).29

Scheme 1. General approaches for THF formation.


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During our investigation on the B(C6F5)3-catalyzed partial and selective deoxygenation of alkenyl sugars,30,31 selective allylic C−O bond cleavage was observed to proceed via an SN2′ type mechanism, and was mediated by a cyclic intermediate that could be independently synthesized and isolated in high yields after treating the starting material with catalytic B(C6F5)3 (Scheme 2(a)).32–35 A similar intramolecular condensation was proposed to be key to the selective removal of a single secondary C−O bond in biomass derived 1,6-deoxytetraols.36 In this case a key silylium-THF intermediate could be independently generated by treating the tetraol with a stoichiometric quantity of in situ generated silylium (R3Si+) provided that the counterion was unreactive (B(C6F5)4–) (Scheme 2(b)).36 The cyclization was regioselective and cleanly inverted the electrofuge at C2 to form a single THF isomer. Based on these results, we initiated a study to purposefully apply B(C6F5)3 or silylium (R3Si+) catalysis to mediate the condensative cyclization of a variety of linear and cyclic sugars.

Scheme 2. Cyclic intermediates in selective hydrosilylative deoxygenation.

RESULTS AND DISCUSSION Our studies initiated with an examination of TMS-galactitol, which consumes the starting material upon treating with 10 mol% B(C6F5)3 in dichloromethane (CH2Cl2) at room temperature (Scheme 3). After TMS removal with Dowex/MeOH the mono-anhydrosugar 137 was obtained in


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ACS Catalysis

87% yield; no other anhydrosugars were detected. Similar to the previously suggested mechanism for THF formation in Scheme 2(a),36 we propose that B(C6F5)3 initiates the reaction by activating one of the symmetry equivalent primary C−O bonds for intramolecular attack by the C4 silyl ether. This generates a borate/silyloxonium ion pair (A) that can extrude (R3Si)2O and generate 1.

Scheme 3. B(C6F5)3-catalyzed intramolecular condensative cyclization. In the scenario in Scheme 3 the borane Lewis acid activates the primary silyl ether for cyclization to A. Several fates are possible for A, however, and these would lead to different propagation mechanisms. If A collapses to (R3Si)2O, B(C6F5)3 and product, then B(C6F5)3 would be a true catalyst. If, on the other hand, A simply serves as a source of R3Si+ to promote further reactions, then B(C6F5)3 is an initiator that forms [R3SiO−B(C6F5)3–] and R3Si+ is the true catalyst. Monitoring the B(C6F5)3 speciation with this query. In situ

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F NMR analysis provided data relevant to

F NMR spectroscopy clearly shows there is no free B(C6F5)3 during the

reaction, and an initially formed B(C6F5)3 derived species (Figure 2(a)) is eventually converted to a second form after 24 h (Figure 2(b)). By comparing in situ spectra with those obtained from a 1:1 mixture of B(C6F5)3 and NaOtBu (a model for siloxide, Figure 2(c)) and a 1:10 mixture of B(C6F5)3 and THF (Figure 2(d)), we conclude that [R3SiO−B(C6F5)3–] is the kinetically


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generated form of the borane (A) after 1 h. Over time, however, it converts to an adduct resembling THF−B(C6F5)3 (B). These NMR data support the formation of intermediate A, and eventually B, as well as supporting the scenario where B(C6F5)3 acts as an initiator. At the 1 hour time point ~15% of [R3SiO−B(C6F5)3–] has already been converted to L−B(C6F5)3 (Figure 2(a)).

Figure 2. 19F NMR spectra with an internal standard (1,2-difluorobenzene, C6H4F2) of (a) the reaction of TMS-galactitol with 10 mol% B(C6F5)3 after 1 h; (b) after 24 h; (c) 1:1 mixture of B(C6F5)3 and NaOtBu; (d) 1:10 mixture of B(C6F5)3 and THF. Since silylium ion equivalents can be generated by the combination of [Ph3C+][B(C6F5)4–] and a silane,38,39 we sought to test whether intentionally generated silylium ions would similarly catalyze the condensative cyclization of linear sugars (CnOn). Persilylated sugars were mixed with [Ph3C+][B(C6F5)4–] in CH2Cl2, and then Me2EtSiH was added to it (details in Table 1). Silane addition bleaches the bright orange color of the trityl cation, and in situ 13C NMR analysis shows that all of the starting material has been converted to a 3,4-dihydroxy-THF (1-5, Table 1).37,40–43 Although these experiments do not distinguish between the two limiting mechanistic scenarios (B catalysis or R3Si+), experiments to be discussed in the following sections have revealed differences between these two protocols that suggest ultimately that both pathways are, in


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principle, feasible. The trityl-based method proved highly effective, so this method was used on several additional poly-ol structures. Table 1. Silylium catalyzed condensation with linear sugars

Our experiments continued with the linear C5O5 sugars. The condensative cyclization of TMSarabitol could either generate a trans- or cis-3,4-dihydroxy product, depending on whether the diastereomeric C1 or C5 positions were activated (Scheme 4). The relevant transition states suggest that formation of the cis-stereoisomer should be slower due to steric clashes between the gauche siloxy groups. Consistent with these predictions, 5 mol% Me2EtSi+ provides trans-3,4dihydroxy 2 as the sole product (Table 1, Entry 1).40 The above reasoning favoring a transselectivity is also in line with the observed sluggish cyclization of TMS-adonitol to 3 (18 h vs. 1


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h for TMS-arabitol),41 which can only give the cis product. Despite the former being considerably slower, both diastereomers are available in high yields (Entries 1 and 2). We also used these substrates to test B(C6F5)3 catalyzed cyclizations, monitoring B(C6F5)3 speciation at early (0.5 h) and later (1 day) time points. Although the yields were a little lower than those under trityl/silane-based conditions (parentheses in Entries 1 and 2), TMS-arabitol and TMSadonitol were successfully converted to 2 and 3 using B(C6F5)3 catalysis. The B(C6F5)3-derived species previously shown to be consistent with [R3SiO−B(C6F5)3–] was also observed after 0.5 h, and, as before, over a day it converts to a THF−B(C6F5)3 adduct, such as B (Scheme 3).

Scheme 4. Competing transition states for the cyclization of asymmetric TMS-arabitol. Next, we tested the silylium catalyzed conditions with the hexitols, TMS-galactitol, TMSsorbitol and TMS-mannitol; each afforded a diastereomerically unique mono-anhydrosugar (1, 4 and 5 in Table 1) as the sole product.37,42,43 In the case of the earlier discussed TMS-galactitol (Entry 3), other larger silyliums, such as Ph3Si+ or Et3Si+, were similarly fast and high yielding and catalyst loadings as low as 2 mol% (Me2EtSi+) were also complete within an hour (not shown). In the cases of slower reacting TMS-sorbitol and TMS-mannitol, higher catalyst loadings and lower reaction temperature improved the yield of products.44 Control experiments using 10 mol% TMSOTf as the silylium source showed no reaction with TMS-galactitol at RT over the course of a day.


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Although the two cyclization regio-directions are symmetry equivalent in the cases of TMSgalactitol and TMS-mannitol, the asymmetric TMS-sorbitol could generate two diastereomers depending on whether O3 cyclizes on to C6 or O4 adds to C1 (Entries 3 & 5 vs. Entry 4). Inhibiting steric interaction in the putative transition states similar to those discussed for TMSarabitol (Scheme 4) may be responsible for the exclusive formation of the 1,4-anhydro-isomer. Most acidic dehydrations of sorbitol typically generate small amounts of 2,5-anhydro- or 3,6anhydrosugars as byproducts.7 For example, under debenzylative condiions, mannitol affords the product of cyclizing O2 onto C5, which is not observed under silylium catalyzed conditions.26 Scheme 5 compares putative transition states for forming the 1,4-anhydro-cis-dihydroxy product (Si-5) and the unobserved 2,5-anhydro-product. The 2-5 forming transition state features large interactions between the O2 & O6 silyl ethers. It also highlights the congestion created on forming cis-dihydroxy products and illustrates the need for the higher catalyst loadings.

Scheme 5. Plausible transition states for silylium catalyzed cyclization of TMS-mannitol. Contrary to the above-mentioned B(C6F5)3 initiated cyclization results with TMS-galactitol and the C5O5 substrates, the more sluggish TMS-sorbitol and TMS-mannitol substrates only partially convert to products at even high loading of B(C6F5)3 (20 mol%). By

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F NMR spectroscopy

[R3SiO−B(C6F5)3–] was observed initially and this eventually converted to a THF−B(C6F5)3 type adduct and (R3Si)2O (24 h). The consumption of silylium in this case correlates to a ceasing of conversion.


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A control experiment with THF−B(C6F5)3 demonstrated that this Lewis adduct is incapable of initiating the condensative cyclization of TMS-galactitol. To the extent that THF itself is a good model for the more complex THFs generated from the poly-ol substrates (i.e. B in Scheme 3), these data, therefore, suggest that the reactions are silylium catalyzed and when the cyclization is relatively slow (e.g. TMS-sorbitol or TMS-mannitol) the initially formed [R3SiO−B(C6F5)3–] may collapse to an unreactive THF−B(C6F5)3 and (R3Si)2O, and thus quench the active silylium. Once a basic THF is paired with the B(C6F5)3, the poorer silyl ether is unable to compete for coordination/activation and the cycle cannot reinitiate. Table 2. Silylium catalyzed condensation with sugar derived tetraols

A similar treatment of a number of partially deoxygenated compounds generated from 1,6deoxygenation of linear hexitol via B(C6F5)3/silane catalysis,36 yielded stereochemically rich 2,5dimethyl-3,4-dihydroxy-THF structures on treating with 10 mol% Me2EtSi+ over 18 h at room temperature followed by in situ deprotection (Table 2). In this manner, the gal-, man- and sor-


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based precursors, respectively, provided THFs displaying the trans-cis-cis (6), cis-trans-trans (7), trans-trans-trans (8a) and cis-trans-cis (8b), diastereomeric array of methyl and hydroxyl groups. The yields ranged from good to excellent (50-94%). Compounds 6 and 8a were previously cyclized with a stoichiometric quantity of silylium in a previous study on the selective and partial deoxygenation of secondary C−O bonds.36 In the latter case, only diastereomer 8a, the product of the preferential cyclization of O5 onto C2, was obtained. Catalytic quantities of [Me2EtSi+][B(C6F5)4–] (10 mol%), however, yields both diastereomers (8a and 8b) in a ~2:1 ratio. Although the transition state to form 8a (TS-I, O2→C5, Scheme 6) looks more favorable on steric grounds, 8b is ~1 kcal/mol more stable according to DFT calculations (ωB97X-D functional with 6-31+G** basis set and CPCM = CH2Cl2). The role of reversibility in such cyclizations has yet to be established. The 3,4deoxymannitol (Entry 4, Table 2), prepared from isomannide via B(C6F5)3/silane catalysis,36 was examined under the trityl/silane-conditions. Despite being slower than the other tetraols in Table 2, the corresponding THF (9) was obtained in 59% yield.

Scheme 6. Transition states of 1,6-deoxysorbitol (Me2EtSi-sor-tetraol). The substrates in Table 2 were also tested with the B(C6F5)3 catalyst. In the presence of 20 mol% B(C6F5)3, each 1,6-deoxytetraol generated the expected products after 46 h at room temperature, except for Me2EtSi-iso-tetraol (incomplete conversion after 3 days). In situ monitoring by

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C{1H} NMR spectroscopy indicated that there were both anionic species


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[R3SiO−B(C6F5)3–] (A, Scheme 3) and THF−B(C6F5)3 type adducts (B, Scheme 3) present in the 19

F NMR spectrum at the 24 h period. That any initiation has occurred suggests B(C6F5)3 can

activate secondary silyl ethers in addition to primary. Next, we wondered how B(C6F5)3 might promote condensation reactions with a partially reduced disaccharide, such as maltitol, which has one glycosidic linkage and three primary C−O bonds. In situ monitoring of a reaction of persilylated maltitol with 20 mol% B(C6F5)3 showed that the disaccharide slowly converted to a mixture of 1,6-anhydroglycopyranose (10) and sorbitol (11) over 72 h (Eq. 1). Mechanistically, such a process can be rationalized by silylium (or B(C6F5)3 to initiate) activation of the anomeric oxygen, followed by O6 ring closure and transfer of silylium to another substrate molecule to turn the cycle over.

The observation of a clean cleavage of the glycosidic linkage stimulated an examination of other cyclic sugars for their ability to yield such bicyclic compounds. Adding 10 mol% Me2EtSiH to the reaction mixture containing TMS-galactose and 5 mol% [Ph3C+][B(C6F5)4–] at room temperature initiates a rapid conversion (0.5 h) to 1,6-anhydrogalactofuranose (12) without any sign of the 1,6-anhydropyranose (Eq 2). Even with in situ

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C{1H} NMR spectroscopic

monitoring at early times, the pyranose was not detected. This outcome was unexpected as TMSgalactose generates both forms in a ratio that is solvent dependent under previously reported TMSOTf-catalyzed conditions.29 In our hands, 10 mol% TMSOTf converts TMS-galactose in CD2Cl2 at RT to a mixture of the furanose (12) and the pyranose (not shown) in ~65% conversion (24 h).


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Testing TMS-glucose under trityl/silane conditions provided a 1:5 mixture of 1,6anhydroglucopyranose (10) and 1,6-anhydroglucofuranose (13) by 1H NMR analysis (Eq. 3). The isomer ratio was not sensitive to solvent or reaction temperatures. When pure Me2EtSi-1,6anhydroglycopyranose (Si-10) was treated with Me2EtSi+, a 1:5 mixture of 10 and 13 was obtained in 65% yield after deprotection. Interestingly, the selectivity reversed for β-1-MeOTES-glucose (10:13 = 2.5:1 by in situ 1H NMR analysis) while α-1-MeO-TES-glucose was significantly slower to convert to the pyranose.45 These observations are consistent with a previously proposed mechanism for forming pyranose and furanose products from a cyclic sugar (Scheme 7),46 as well as our observations on anomeric cleavage by B/SiH catalysis.47–49 In a nutshell, with a persilylated cyclic sugar, the higher basicity of the ring ether enhances pyranose ring opening, which initiates 1,6-anhydrofuranose formation. However, more basic glycosidic oxygens increase the propensity to form cyclic oxocarbeniums, which initiates the alternative pathway. The di-, tri- and oligosaccharides in Table 3 provide the same mixture of 10 and 13 in ~1:5 ratio though in diminished yields (28-34%) under trityl/silane conditions. The observed 1:5 ratio of 10 and 13 across multiple conditions suggests that the product distribution is under thermodynamic control.


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Scheme 7. Proposed mechanism and free diagram for 1,6-anhydrohexo-pyranose and furanose; (a) proposed mechanisms (b) ground state energies for 1,6-anhydrosugars; The free energies report in b) were computed by DFT (M06-2X/ 6-31+G(d,p), CPCM CH2Cl2)


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Table 3. Silylium catalyzed condensation of gluco-saccharides

Summary B(C6F5)3 is a convenient catalyst for the condensative cyclization of persilylated linear sugars such as galactitol, sorbitol, and mannitol to the mono-anhydrous diastereomeric 2,3-dihydroxyTHFs. It initiates the reactions by activating the primary siloxy group and promoting an intramolecular addition by a silyl ether to form [R3SiO−B(C6F5)3–] and a silylium-coordinated cyclic ether. The most efficient means for the reaction to turn over is to transfer the silylium to the primary position of a new substrate. Mechanistic studies suggest that the key catalytic silylium is quenched when the reactive ion pair inevitably collapses to (R3Si)2O and a THF−B(C6F5)3 adduct of the product. Even more efficient was the intentionally generated [R3Si+][B(C6F5)4–] catalysts, which regio- and stereoselectively cyclizes C6O6, C5O5, and C6O4 polyols into THF-containing structures. When the starting materials are cyclic sugars, bicyclic


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anhydrosugars are generated in high yields and at high rates. Although the yields suffer, di-, triand oligo-gluco-saccharides are able to provide the same results as persilyl glucose itself, affording a 5:1 mixture of the pyranose and furanose. The data generated from this study suggests that direct C−O activation by B(C6F5)3 and R3Si+ are each possible, both at primary and secondary positions, but that silylium catalysts are the more active of the two and that B(C6F5)3 can initiate catalysis by generating silylium. Supporting Information. The supporting information is available free of charge on the ACS Publications website at DOI: Experimental procedure for silylium catalyzed cyclization and NMR spectra of persilylated sugars, as well as anhydrosugars (1-9, Si-10, Si-11 and 12). Computational details for Si-8a, Si8b, Si-10, Si-11, Si-12, and Si-1,6-galactopyranose in Scheme 7 are included. AUTHOR INFORMATION Corresponding Author *E-mail for M. R. G.: [email protected] Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes The authors declare no competing financial interest. ACKNOWLEDGMENT


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This work was exclusively supported by the Department of Energy (Basic Energy Science, DEFG02-05ER15630). We thank Christina Roselli and Jared Lowe for performing DFT calculations. ABBREVIATIONS Si, silyl protecting groups (either TMS or Me2EtSi); TMS, trimethylsilyl. REFERENCES (1)

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Silylium (R3Si+) Catalyzed Condensative Cyclization for

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